Benzazepine derivatives for the treatment of neurological disorders

ABSTRACT

The present invention relates to novel benzazepine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.10/539,385 filed on Jun. 16, 2005; which is a U.S. National PhaseApplication of International Application No. PCT/EP2003/014556 filed onDec. 18, 2003; which claims priority from Application No. GB0312607.5filed on Jun. 2, 2003 and Application No. GB0229820.6 filed on Dec. 20,2002; all of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to novel benzazepine derivatives havingpharmacological activity, processes for their preparation, tocompositions containing them and to their use in the treatment ofneurological and psychiatric disorders.

BACKGROUND OF THE INVENTION

JP 2001226269 and WO 00/23437 (Takeda Chem Ind Ltd) describe a series ofbenzazepine derivatives which are claimed to be useful in the treatmentof obesity. DE 2207430, U.S. Pat. No. 4,210,749 and FR 2171879 (PennwaltCorp) and GB 1268243 (Wallace and Tiernan Inc) all describe a series ofbenzazepine derivatives which are claimed as being antagonists fornarcotics (such as morphine or codeine) and also anti-histamines andanticholinergic agents. WO 02/14513 (Takeda Chem Ind Ltd) describe aseries of benzazepine derivatives with GPR12 activity which are claimedto be useful in the treatment of attention deficit disorder, narcolepsyor anxiety. WO 02/02530 (Takeda Chem Ind Ltd) describe a series ofbenzazepine derivatives as GPR14 antagonists which are claimed to beuseful in the treatment of hypertension, atherosclerosis and cardiacinfarction. WO 01/03680 (Isis Innovation Ltd) describe a series ofbenzazepine derivatives which are claimed as effective agents in thepreparation of cells for transplantation in addition to the inhibitionof diseases such as diabetes. WO 00/21951 (SmithKline Beecham plc)discloses a series of tetrahydrobenzazepine derivatives as modulators ofdopamine D3 receptors which are claimed to be useful as antipsychoticagents. WO 01/87834 (Takeda Chem Ind Ltd) describe a series ofbenzazepine derivatives as MCH antagonists which are claimed to beuseful in the treatment of obesity. WO 02/15934 (Takeda Chem Ind Ltd)describe a series of benzazepine derivatives as urotensin II receptorantagonists which are claimed to be useful in the treatment ofneurodegenerative disorders.

The histamine H3 receptor is predominantly expressed in the mammaliancentral nervous system (CNS), with minimal expression in peripheraltissues except on some sympathetic nerves (Leurs et al., (1998), TrendsPharmacol. Sci. 19, 177-183). Activation of H3 receptors by selectiveagonists or histamine results in the inhibition of neurotransmitterrelease from a variety of different nerve populations, includinghistaminergic and cholinergic neurons (Schlicker et al., (1994), Fundam.Clin. Pharmacol. 8, 128-137). Additionally, in vitro and in vivo studieshave shown that H3 antagonists can facilitate neurotransmitter releasein brain areas such as the cerebral cortex and hippocampus, relevant tocognition (Onodera et al., (1998), In: The Histamine H3 receptor, edLeurs and Timmerman, pp 255-267, Elsevier Science B.V.). Moreover, anumber of reports in the literature have demonstrated the cognitiveenhancing properties of H3 antagonists (e.g. thioperamide, clobenpropit,ciproxifan and GT-2331) in rodent models including the five choice task,object recognition, elevated plus maze, acquisition of novel task andpassive avoidance (Giovanni et al., (1999), Behav. Brain Res. 104,147-155). These data suggest that novel H3 antagonists and/or inverseagonists such as the current series could be useful for the treatment ofcognitive impairments in neurological diseases such as Alzheimer'sdisease and related neurodegenerative disorders.

SUMMARY OF THE INVENTION

The present invention provides, in a first aspect, a compound of formula(I) or a pharmaceutically acceptable salt thereof:

wherein:R¹ represents —C₃₋₇ cycloalkyl optionally substituted by C₁₋₃ alkyl;R² represents hydrogen, —C₁₋₆ alkyl, —X—C₃₋₈ cycloalkyl, —X-aryl,—X-heterocyclyl, —X-heteroaryl, —X—C₃₋₈ cycloalkyl-Y—C₃₋₈ cycloalkyl,—X—C₃₋₈ cycloalkyl-Y-aryl, —X—C₃₋₈ cycloalkyl-Y-heteroaryl, —X—C₃₋₈cycloalkyl-Y-heterocyclyl, —X-aryl-Y—C₃₋₈ cycloalkyl, —X-aryl-Y-aryl,—X-aryl-Y-heteroaryl, —X-aryl-Y-heterocyclyl, —X-heteroaryl-Y—C₃₋₈cycloalkyl, —X-heteroaryl-Y-aryl, —X-heteroaryl-Y-heteroaryl,—X-heteroaryl-Y-heterocyclyl, —X-heterocyclyl-Y—C₃₋₈ cycloalkyl,—X-heterocyclyl-Y-aryl, —X-heterocyclyl-Y-heteroaryl,—X-heterocyclyl-Y-heterocyclyl;X represents a bond or C₁₋₆ alkyl;Y represents a bond, C₁₋₆ alkyl, CO, COC₂₋₆ alkenyl, O or SO₂;R³ represents halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, amino ortrifluoromethyl;n is 0, 1 or 2;wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groupsof R² may be optionally substituted by one or more substituents (eg. 1,2 or 3) which may be the same or different, and which are selected fromthe group consisting of halogen, hydroxy, cyano, nitro, ═O,trifluoromethyl, trifluoromethoxy, fluoromethoxy, difluoromethoxy, C₁₋₆alkyl, pentafluoroethyl, C₁₋₆ alkoxy, arylC₁₋₆ alkoxy, C₁₋₆ alkylthio,C₁₋₆ alkoxyC₁₋₆ alkyl, C₃₋₇ cycloalkylC₁₋₆ alkoxy, C₁₋₆ alkanoyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyloxy, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, sulfonyl, arylsulfonyl,arylsulfonyloxy, arylsulfonylC₁₋₆ alkyl, aryloxy, C₁₋₆ alkylsulfonamido,C₁₋₆ alkylamino, C₁₋₆ alkylamido, —R⁴, —CO₂R⁴, —COR⁴, C₁₋₆alkylsulfonamidoC₁₋₆ alkyl, C₁₋₆ alkylamidoC₁₋₆ alkyl, arylsulfonamido,arylcarboxamido, arylsulfonamidoC₁₋₆ alkyl, arylcarboxamidoC₁₋₆ alkyl,aroyl, aroylC₁₋₆ alkyl, arylC₁₋₆ alkanoyl, or a group —NR⁵R⁶, —C₁₋₆alkyl-NR⁵R⁶, —C₃₋₈ cycloalkyl-NR⁵R⁶, —CONR⁵R⁶, —NR⁵COR⁶, —NR⁵SO₂R⁶,—OCONR⁵R⁶, —NR⁵CO₂R⁶, —NR⁴CONR⁵R⁶ or —SO₂NR⁵R⁶ (wherein R⁴, R⁵ and R⁶independently represent hydrogen, C₁₋₆ alkyl, —C₃₋₈ cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, aryl, heterocyclyl or heteroaryl or —NR⁵R⁶ mayrepresent a nitrogen containing heterocyclyl group, wherein said R⁴, R⁵and R⁶ groups may be optionally substituted by one or more substituents(eg. 1, 2 or 3) which may be the same or different, and which areselected from the group consisting of halogen, hydroxy, C₁₋₆ alkyl, C₁₋₆alkoxy, cyano, amino, ═O or trifluoromethyl); or solvates thereof.

In one particular aspect of the present invention, there is provided acompound of formula (I) as defined above wherein:

R² represents —C₁₋₆ alkyl, —X—C₃₋₈ cycloalkyl, —X-aryl, —X-heterocyclyl,—X-heteroaryl, —X—C₃₋₈ cycloalkyl-Y—C₃₋₈ cycloalkyl, —X—C₃₋₈cycloalkyl-Y-aryl, —X—C₃₋₈ cycloalkyl-Y-heteroaryl, —X—C₃₋₈cycloalkyl-Y-heterocyclyl, —X-aryl-Y—C₃₋₈ cycloalkyl, —X-aryl-Y-aryl,—X-aryl-Y-heteroaryl, —X-aryl-Y-heterocyclyl, —X-heteroaryl-Y—C₃₋₈cycloalkyl, —X-heteroaryl-Y-aryl, —X-heteroaryl-Y-heteroaryl,—X-heteroaryl-Y-heterocyclyl, —X-heterocyclyl-Y—C₃₋₈ cycloalkyl,—X-heterocyclyl-Y-aryl, —X-heterocyclyl-Y-heteroaryl,—X-heterocyclyl-Y-heterocyclyl; andY represents a bond, C₁₋₆ alkyl, CO, O or SO₂; andR⁴, R⁵ and R⁶ independently represent hydrogen, C₁₋₆ alkyl, —C₃₋₈cycloalkyl, aryl, heterocyclyl or heteroaryl or —NR⁵R⁶ may represent anitrogen containing heterocyclyl group.

DETAILED DESCRIPTION OF THE INVENTION

A specific set of compounds of formula (I) which may be mentioned arethose wherein R² represents —X-heterocyclyl, —X-heterocyclyl-Y—C₃₋₈cycloalkyl, —X-heterocyclyl-Y-aryl, —X-heterocyclyl-Y-heteroaryl or—X-heterocyclyl-Y-heterocyclyl and said heterocyclyl groups are attachedto X via a carbon atom.

Alkyl groups, whether alone or as part of another group, may be straightchain or branched and the groups alkoxy and alkanoyl shall beinterpreted similarly. Alkyl moieties are more preferably C₁₋₄ alkyl,eg. methyl or ethyl. The term ‘halogen’ is used herein to describe,unless otherwise stated, a group selected from fluorine, chlorine,bromine or iodine.

References to ‘aryl’ include references to monocyclic carbocyclicaromatic rings (eg. phenyl) and bicyclic carbocyclic aromatic rings(e.g. naphthyl) or carbocyclic benzofused rings (eg. C₃₋₈ cycloalkylfused to a phenyl ring, such as dihydroindenyl ortetrahydronaphthalenyl).

The term “heterocyclyl” is intended to mean a 4-7 membered monocyclicsaturated or partially unsaturated aliphatic ring or a 4-7 memberedsaturated or partially unsaturated aliphatic ring fused to a benzenering containing 1 to 3 heteroatoms selected from oxygen, nitrogen orsulphur. Suitable examples of such monocyclic rings includepyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydrofuranyl, tetrahydropyranyl, diazepanyl, azepanyl,imidazolidinyl, isothiazolidinyl, oxazolidinyl, pyrrolidinone andtetrahydro-oxazepinyl. Suitable examples of benzofused heterocyclicrings include indolinyl, isoindolinyl, benzodioxolyl, dihydroisoindole,dihydrobenzofuranyl, dihydrobenzothiopyranyl and dihydroisoquinolinyl.

The term “nitrogen containing heterocyclyl” is intended to represent anyheterocyclyl group as defined above which contains a nitrogen atom.

The term “heteroaryl” is intended to mean a 5-7 membered monocyclicaromatic or a fused 8-11 membered bicyclic aromatic ring containing 1 to3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitableexamples of such monocyclic aromatic rings include thienyl, furyl,pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl,isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl,pyridazinyl, pyrazinyl, pyridyl and tetrahydropyranyl. Suitable examplesof such fused aromatic rings include benzofused aromatic rings such asquinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl,naphthyridinyl, indolyl, indazolyl, furopyridinyl, pyrrolopyridinyl,benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl,benzothiadiazolyl and the like.

Preferably, R¹ represents unsubstituted —C₃₋₇ cycloalkyl (eg.cyclobutyl, cyclopentyl or cyclohexyl). Also preferably, R¹ represents—C₃₋₇ cycloalkyl (eg. cyclopentyl) substituted by a C₁₋₃ alkyl (eg.methyl) group.

Most preferably, R¹ represents unsubstituted cyclobutyl or cyclopentyl,especially unsubstituted cyclobutyl.

Preferably, R² represents

-   -   hydrogen;    -   —C₁₋₆ alkyl (eg. methyl or propyl) optionally substituted by a        —CO₂R⁴ or —CONR⁵R⁶ group;    -   —X—C₃₋₈ cycloalkyl-Y-heterocyclyl (eg.        —X-cyclohexyl-Y-morpholinyl);    -   —X-aryl (eg. —X-phenyl) optionally substituted by one or two        halogen (eg. fluorine, iodine or chlorine), C₁₋₆ alkyl (eg.        methyl), C₁₋₆ alkoxy (eg. methoxy), —CO₂R⁴, —CONR⁵R⁶, —NR⁵COR⁶,        —SO₂NR⁵R⁶ or cyano groups;    -   —X-aryl-Y-heterocyclyl (eg. —X-phenyl-Y-piperazinyl,        —X-phenyl-Y-pyrrolidinyl or —X-phenyl-Y-morpholinyl) optionally        substituted by one or two ═O, halogen (eg. fluorine) or R⁴        groups;    -   —X-heteroaryl (eg. —X-pyridinyl, —X-pyrazinyl, —X-pyrimidinyl,        —X-pyridazinyl, —X-quinolinyl, —X-pyrrolopyridinyl,        —X-furopyridinyl, —X-naphthyridinyl, —X-thiazolyl or —X-thienyl)        optionally substituted by one or two halogen (eg. bromine or        iodine), C₁₋₆ alkyl (eg. methyl), C₁₋₆ alkoxy (eg. methoxy or        ethoxy), cyano, nitro, —OR⁴, —COR⁴, —CO₂R⁴, —NR⁵R⁶, —NR⁵COR⁶,        —CONR⁵R⁶ or ═O groups;    -   —X-heteroaryl-Y-aryl (eg. —X-pyrazinyl-Y-phenyl) optionally        substituted by a C₁₋₆ alkylsulfonyl (eg. —SO₂Me) or —NR⁵COR⁶        group;    -   —X-heteroaryl-Y-heteroaryl (eg. —X-pyridinyl-Y-pyrazolyl,        —X-pyridinyl-Y-oxadiazolyl, —X-pyridinyl-Y-oxazolyl or        —X-pyridinyl-Y-pyrazinyl) optionally substituted by a C₁₋₆ alkyl        (eg. methyl) group;    -   —X-heteroaryl-Y-heterocyclyl (eg. —X-pyridinyl-Y-morpholinyl,        —X-pyridinyl-Y-pyrrolidinyl, —X-pyridinyl-Y-piperidinyl,        —X-pyridinyl-Y-thiomorpholinyl,        —X-pyridinyl-Y-tetrahydropyranyl, —X-pyridinyl-Y-imidazolidinyl,        —X-pyridinyl-Y-tetrahydro-oxazepinyl, —X-pyridinyl-Y-azetidinyl,        —X-pyridinyl-Y-oxazolidinyl, —X-pyridinyl-Y-isothiazolidinyl,        —X-pyrazinyl-Y-morpholinyl, —X-pyrazinyl-Y-piperidinyl,        —X-pyrazinyl-Y-pyrrolidinyl, —X-pyrazinyl-Y-thiomorpholinyl,        —X-pyrazinyl-Y-oxazolidinyl, —X-pyrazinyl-Y-azetidinyl,        —X-pyrazinyl-Y-tetrahydropyranyl or        —X-pyridazinyl-Y-morpholinyl) optionally substituted by one or        two ═O, C₁₋₆ alkyl (eg. methyl), —OR⁴ or halogen (eg. chlorine        or bromine) groups;    -   —X-heterocyclyl (eg. —X-piperidinyl or —X-pyrrolidinyl)        optionally substituted by a C₁₋₆ alkylsulfonyl (eg. —SO₂Me),        C₁₋₆ alkoxycarbonyl (eg. —CO—CH₂CH₂OMe), —CO₂R⁴, —COR⁴ or        —COR⁵R⁶ group;    -   —X-heterocyclyl-Y-aryl (eg. —X-piperidinyl-Y-phenyl or        —X-pyrrolidinyl-Y-phenyl) optionally substituted by a halogen        (eg. fluorine), cyano, C₁₋₆ alkylsulfonyl (eg —SO₂Me), R⁴ or        —CONR⁵R⁶ group;    -   —X-heterocyclyl-Y-heterocyclyl (eg.        —X-piperidinyl-Y-tetrahydropyranyl,        —X-pyrrolidinyl-Y-tetrahydropyranyl,        —X-piperidinyl-Y-dihydrobenzofuranyl,        —X-pyrrolidinyl-Y-morpholinyl, —X-piperidinyl-Y-morpholinyl,        —X-piperidinyl-Y-thiomorpholinyl,        —X-piperidinyl-Y-dihydroisoindole, —X-piperidinyl-Y-piperazinyl,        —X-piperidinyl-Y-pyrrolidinyl, —X-piperidinyl-Y-piperidinyl or        —X-piperidinyl-Y-dihydrobenzothiopyranyl) optionally substituted        by one or two ═O or R⁴ groups;    -   —X-heterocyclyl-Y—C₃₋₈ cycloalkyl (eg.        —X-piperidinyl-Y-cyclohexyl, —X-piperidinyl-Y-cyclopropyl,        —X-piperidinyl-Y-cyclobutyl or —X-piperidinyl-Y-cyclopentyl); or    -   —X-heterocyclyl-Y-heteroaryl (eg.        —X-piperidinyl-Y-isoquinolinyl, —X-piperidinyl-Y-quinolinyl,        —X-piperidinyl-Y-isoxazolyl, —X-piperidinyl-Y-benzothiazolyl,        —X-piperidinyl-Y-thiophenyl, —X-piperidinyl-Y-furanyl,        —X-piperidinyl-Y-pyrazinyl, —X-piperidinyl-Y-pyridyl) optionally        substituted by one or two C₁₋₆ alkyl (eg. methyl), ═O, cyano or        —CONR⁵R⁶ groups.

Preferably, X represents a bond or —CH₂—, most preferably X represents abond.

Preferably, Y represents a bond, CO, SO₂ or —CO—CH═CH— most preferably Yrepresents a bond or CO, especially a bond.

Preferably, R⁴ represents hydrogen, C₁₋₆ alkyl (eg. methyl, ethyl ort-butyl), —C₁₋₆ alkyl-C₃₋₈ cycloalkyl (eg. —CH₂cyclopropyl), aryl (eg.phenyl optionally substituted by a halogen atom (eg. fluorine),heterocyclyl (eg. morpholinyl) or heteroaryl (eg. pyridinyl orpyrazinyl) optionally substituted by a halogen (eg. fluorine) or C₁₋₆alkoxy (eg. methoxy) group.

Preferably, R⁵ and R⁶ independently represent hydrogen, C₁₋₆ alkyl (eg.methyl, ethyl, isopropyl or propyl), —C₃₋₈ cycloalkyl (eg. cyclobutyl orcyclopentyl), —C₁₋₆ alkyl-C₃₋₈ cycloalkyl (eg. —CH₂-cyclopropyl),heterocyclyl (eg. pyrrolidinyl, piperidinyl, morpholinyl ortetrahydropyranyl) or aryl (eg. phenyl) optionally substituted by ahalogen (eg. fluorine), cyano or C₁₋₆ alkoxy (eg. methoxy) group or—NR⁵R⁶ represents a nitrogen containing heterocyclyl group (eg.azetidinyl, morpholinyl, pyrrolidinyl or piperidinyl) optionallysubstituted by one or two ═O groups.

More preferably, R⁵ and R⁶ independently represent hydrogen, C₁₋₆ alkyl(eg. methyl or ethyl), —C₃₋₈ cycloalkyl (eg. cyclobutyl or cyclopentyl)or —C₁₋₆ alkyl-C₃₋₈ cycloalkyl (eg. —CH₂-cyclopropyl).

Particularly preferably, R² represents

-   -   hydrogen;    -   —C₁₋₆ alkyl (eg. methyl or propyl) optionally substituted by a        —CO₂R⁴ (eg. —CO₂Et or —CO₂H) or —CONR⁵R⁶ (eg. —CO N(Me)₂, —CO        N(H)(Me), —CON(H)(cyclopentyl), —CO N(H)(phenyl),        —CO-pyrrolidinyl, —CO-piperidinyl or —CO-morpholinyl) group;    -   —X—C₃₋₈ cycloalkyl-Y-heterocyclyl (eg.        -cyclohexyl-CO-morpholinyl);    -   —X-aryl (eg. -phenyl or —CH₂-phenyl) optionally substituted by        one or two halogen (eg. fluorine, iodine or chlorine), C₁₋₆        alkyl (eg. methyl), C₁₋₆ alkoxy (eg. methoxy), —CO₂R⁴ (eg. —CO₂H        or —CO₂Me), —CONR⁵R⁶ (eg. —CON(H)(Me), —CON(Et)₂ (optionally        substituted by a methoxy group), —CON(Me)(Pr) substituted by a        cyano group) or —CON(H)(—CH₂-cyclopropyl), —NR⁵COR⁶ (eg.        —NHCOMe), —SO₂NR⁵R⁶ (eg. —SO₂N(Et)₂) or cyano groups;    -   —X-aryl-Y-heterocyclyl (eg. -phenyl-pyrrolidinyl,        -phenyl-CO-pyrrolidinyl, -phenyl-CO-morpholinyl,        -phenyl-SO₂-morpholinyl, —CH₂-phenyl-CO-pyrrolidinyl,        —CH₂-phenyl-CO-morpholinyl or —CH₂-phenyl-CO-piperazinyl)        optionally substituted by one or two ═O, halogen (eg. fluorine)        or R⁴ (eg. phenyl (optionally substituted by a fluorine atom) or        pyridyl) groups;    -   —X-heteroaryl (eg. -pyridinyl, —CH₂-pyridinyl, -pyrazinyl,        -pyrimidinyl, -pyridazinyl, -quinolinyl, —CH₂-quinolinyl,        -pyrrolopyridinyl, -furopyridinyl, -naphthyridinyl, -thiazolyl        or -thienyl) optionally substituted by one or two halogen (eg.        bromine or iodine), C₁₋₆ alkyl (eg. methyl), C₁₋₆ alkoxy (eg.        methoxy or ethoxy), cyano, nitro, —OR⁴ (eg. hydroxy), —CO₂R⁴        (eg. CO₂H or CO₂Me), —COR⁴ (eg. COMe), —NR⁵R⁶ (eg. —NH₂ or        —N(H)(Me)), —NR⁵COR⁶ (eg. NHCOMe, NHCO-i-Pr, —NHCO-pyrrolidinyl,        —NHCO-piperidinyl, —NHCO-morpholinyl or        —NHCO-tetrahydropyranyl), —CONR⁵R⁶ (eg. —CONH₂, —CON(Me)₂,        —CON(Me)(Et), —CON(H)(Me), —CON(H)(i-Pr), —CON(Et)₂ (optionally        substituted by a methoxy group), —CON(H)(Et) (optionally        substituted by a methoxy group), —CON(H)(—CH₂cyclopropyl),        —CON(H)(cyclobutyl), —CON(H)(cyclopentyl), —CON(H)(cyclopropyl)        or —CON(H)(tetrahydropyranyl)) or ═O groups;    -   —X-heteroaryl-Y-aryl (eg. -pyrazinyl-phenyl) optionally        substituted by a C₁₋₆ alkylsulfonyl (eg. —SO₂Me) or —NR⁵COR⁶        (eg. —NHCOMe) group;    -   —X-heteroaryl-Y-heteroaryl (eg. -pyridinyl-pyrazolyl,        -pyridinyl-oxadiazolyl, -pyridinyl-oxazolyl or        -pyridinyl-pyrazinyl) optionally substituted by a C₁₋₆ alkyl        (eg. methyl) group;    -   —X-heteroaryl-Y-heterocyclyl (eg. -pyridinyl-CO-morpholinyl,        -pyridinyl-CO-pyrrolidinyl, -pyridinyl-CO-piperidinyl,        -pyridinyl-CO-thiomorpholinyl, -pyridinyl-imidazolidinyl,        -pyridinyl-CO-tetrahydro-oxazepinyl, -pyridinyl-CO-azetidinyl,        -pyridinyl-oxazolidinyl, -pyridinyl-isothiazolidinyl,        -pyrazinyl-morpholinyl, -pyrazinyl-CO-morpholinyl,        -pyrazinyl-CO-piperidinyl, -pyrazinyl-CO-pyrrolidinyl,        -pyrazinyl-thiomorpholinyl, -pyrazinyl-oxazolidinyl,        -pyrazinyl-CO-azetidinyl, -pyrazinyl-piperidinyl,        -pyrazinyl-pyrrolidinyl, -pyridinyl-pyrrolidinyl,        -pyridinyl-piperidinyl, -pyridinyl-SO₂-morpholinyl or        -pyridazinyl-CO-morpholinyl) optionally substituted by one or        two ═O, C₁₋₆ alkyl (eg. methyl), —OR⁴ (eg. hydroxy) or halogen        (eg. chlorine or bromine) groups;    -   —X-heterocyclyl (eg. -piperidinyl, —CH₂-piperidinyl,        -pyrrolidinyl or —CH₂-pyrrolidinyl) optionally substituted by a        C₁₋₆ alkylsulfonyl (eg. —SO₂Me), C₁₋₆ alkoxycarbonyl (eg.        —CO—CH₂CH₂OMe), —CO₂R⁴ (eg. —CO₂-t-Bu)—COR⁴ (eg.        —COCH₂cyclopropyl) or —COR⁵R⁶ (eg. —CON(i-Pr)₂, —CON(Et)₂,        —CON(i-Pr)(Et) (substituted by a methoxy group), —CON(H)(i-Pr)        or —CON(H)(4-fluorophenyl) group;    -   —X-heterocyclyl-Y-aryl (eg. -piperidinyl-CO-phenyl,        -pyrrolidinyl-CO-phenyl, -piperidinyl-CO—CH═CH-phenyl,        -piperidinyl-SO₂-phenyl, pyrrolidinyl-SO₂-phenyl,        —CH₂-piperidinyl-CO-phenyl, —CH₂-pyrrolidinyl-CO-phenyl,        —CH₂-piperidinyl-SO₂-phenyl or —CH₂-pyrrolidinyl-SO₂-phenyl)        optionally substituted by a halogen (eg. fluorine), cyano, C₁₋₆        alkylsulfonyl (eg —SO₂Me), R⁴ (eg. phenyl or morpholinyl) or        —CONR⁵R⁶ (eg. —CO-pyrrolidinyl substituted by an ═O group)        group;    -   —X-heterocyclyl-Y-heterocyclyl (eg.        -piperidinyl-CO-tetrahydropyranyl,        —CH₂-piperidinyl-CO-tetrahydropyranyl,        -pyrrolidinyl-CO-tetrahydropyranyl,        —CH₂-pyrrolidinyl-CO-tetrahydropyranyl,        -piperidinyl-CO-dihydrobenzofuranyl,        -pyrrolidinyl-CO-morpholinyl, —CH₂-pyrrolidinyl-CO-morpholinyl,        -piperidinyl-CO-morpholinyl, —CH₂-piperidinyl-CO-morpholinyl,        -piperidinyl-CO-thiomorpholinyl,        -piperidinyl-CO-dihydroisoindole, -piperidinyl-CO-piperazinyl,        —piperidinyl-CO-pyrrolidinyl, -piperidinyl-CO-piperidinyl or        -piperidinyl-CO-dihydrobenzothiopyranyl) optionally substituted        by one or two ═O or R⁴ (eg. pyrazinyl) groups;    -   —X-heterocyclyl-Y—C₃₋₈ cycloalkyl (eg.        -piperidinyl-CO-cyclohexyl, -piperidinyl-CO-cyclopropyl,        -piperidinyl-CO-cyclobutyl or -piperidinyl-CO-cyclopentyl); or    -   —X-heterocyclyl-Y-heteroaryl (eg. -piperidinyl-CO-isoquinolinyl,        -piperidinyl-CO-quinolinyl, -piperidinyl-CO-isoxazolyl,        -piperidinyl-SO₂-isoxazolyl, -piperidinyl-CO-benzothiazolyl,        -piperidinyl-CO-thiophenyl, -piperidinyl-CO-furanyl,        -piperidinyl-CO-pyrazinyl, -piperidinyl-pyrazinyl,        -piperidinyl-CO-pyridinyl or -piperidinyl-pyridinyl) optionally        substituted by one or two C₁₋₆ alkyl (eg. methyl), ═O, cyano or        —CONR⁵R⁶ (eg. —CON(H)(Me), —CON(H)(—CH₂cyclopropyl),        —CO-azetidinyl or —CO-morpholinyl) groups.

More preferably, R² represents

-   -   —X-aryl (eg. phenyl) optionally substituted by a CONR⁵R⁶ group;    -   —X-aryl-Y-heterocyclyl (eg. —X-phenyl-Y-morpholinyl or        —X-phenyl-Y-pyrrolidinyl);    -   —X-heteroaryl (eg. pyrazinyl or pyridinyl) optionally        substituted by a CONR⁵R⁶ group;    -   —X-heteroaryl-Y-heterocyclyl (eg. —X-pyridinyl-Y-morpholinyl,        —X-pyridinyl-Y-pyrrolidinyl,    -   —X-pyridinyl-Y-piperidinyl, —X-pyridinyl-Y-thiomorpholinyl,        —X-pyrazinyl-Y-morpholinyl, —X-pyrazinyl-Y-piperidinyl or        —X-pyrazinyl-Y-pyrrolidinyl) optionally substituted by one or        two ═O groups; or    -   —X-heterocyclyl-Y-heterocyclyl (eg.        —X-piperidinyl-Y-tetrahydropyranyl, —X-piperidinyl-Y-morpholinyl        or —X-pyrrolidinyl-Y-morpholinyl).

Yet more preferably, R² represents

-   -   —X-aryl (eg. -phenyl or —CH₂-phenyl) optionally substituted by        one or two halogen (eg. fluorine, iodine or chlorine), C₁₋₆        alkyl (eg. methyl), C₁₋₆ alkoxy (eg. methoxy), —CO₂R⁴ (eg. —CO₂H        or —CO₂Me), —CONR⁵R⁶ (eg. —CON(H)(Me), —CON(Et)₂ (optionally        substituted by a methoxy group), —CON(Me)(Et) substituted by a        cyano group) or —CON(H)(—CH₂-cyclopropyl), —NR⁵COR⁶ (eg.        —NHCOMe), —SO₂NR⁵R⁶ (eg. —SO₂N(Et)₂) or cyano groups;    -   —X-aryl-Y-heterocyclyl (eg. -phenyl-pyrrolidinyl,        -phenyl-CO-pyrrolidinyl, -phenyl-CO-morpholinyl,        -phenyl-SO₂-morpholinyl, —CH₂-phenyl-CO-pyrrolidinyl,        —CH₂-phenyl-CO-morpholinyl or —CH₂-phenyl-CO-piperazinyl)        optionally substituted by one or two ═O, halogen (eg. fluorine)        or R⁴ (eg. phenyl (optionally substituted by a fluorine atom) or        pyridyl) groups;    -   —X-heteroaryl (eg. -pyridinyl, —CH₂-pyridinyl, -pyrazinyl,        -pyrimidinyl, -pyridazinyl, -quinolinyl, —CH₂-quinolinyl,        -pyrrolopyridinyl, -furopyridinyl, -naphthyridinyl, -thiazolyl        or -thienyl) optionally substituted by one or two halogen (eg.        bromine or iodine), C₁₋₆ alkyl (eg. methyl), C₁₋₆ alkoxy (eg.        methoxy or ethoxy), cyano, nitro, —OR⁴ (eg. hydroxy), —CO₂R⁴        (eg. CO₂H or CO₂Me), —COR⁴ (eg. COMe), —NR⁵R⁶ (eg. —NH₂ or        —N(H)(Me)), —NR⁵COR⁶ (eg. NHCOMe, NHCO-i-Pr, —NHCO-pyrrolidinyl,        —NHCO-piperidinyl, —NHCO-morpholinyl or        —NHCO-tetrahydropyranyl), —CONR⁵R⁶ (eg. —CONH₂, —CON(Me)₂,        —CON(Me)(Et), —CON(H)(Me), —CON(H)(i-Pr), —CON(Et)₂ (optionally        substituted by a methoxy group), —CON(H)(Et) (optionally        substituted by a methoxy group), —CON(H)(—CH₂cyclopropyl),        —CON(H)(cyclobutyl), —CON(H)(cyclopentyl), —CON(H)(cyclopropyl)        or —CON(H)(tetrahydropyranyl)) or ═O groups;    -   —X-heteroaryl-Y-heterocyclyl (eg. -pyridinyl-CO-morpholinyl,        -pyridinyl-CO-pyrrolidinyl, -pyridinyl-CO-piperidinyl,        -pyridinyl-CO-thiomorpholinyl, -pyridinyl-imidazolidinyl,        -pyridinyl-CO-tetrahydro-oxazepinyl, -pyridinyl-CO-azetidinyl,        -pyridinyl-oxazolidinyl, -pyridinyl-isothiazolidinyl,        -pyrazinyl-morpholinyl, -pyrazinyl-CO-morpholinyl,        -pyrazinyl-CO-piperidinyl, -pyrazinyl-CO-pyrrolidinyl,        -pyrazinyl-thiomorpholinyl, -pyrazinyl-oxazolidinyl,        -pyrazinyl-CO-azetidinyl, -pyrazinyl-piperidinyl,        -pyrazinyl-pyrrolidinyl, -pyridinyl-pyrrolidinyl,        -pyridinyl-piperidinyl, -pyridinyl-SO₂-morpholinyl or        -pyridazinyl-CO-morpholinyl) optionally substituted by one or        two ═O, C₁₋₆ alkyl (eg. methyl), —OR⁴ (eg. hydroxy) or halogen        (eg. chlorine or bromine) groups; or    -   —X-heterocyclyl-Y-heterocyclyl (eg.        -piperidinyl-CO-tetrahydropyranyl,        —CH₂-piperidinyl-CO-tetrahydropyranyl,        -pyrrolidinyl-CO-tetrahydropyranyl,        —CH₂-pyrrolidinyl-CO-tetrahydropyranyl,        -piperidinyl-CO-dihydrobenzofuranyl,        -pyrrolidinyl-CO-morpholinyl, —CH₂-pyrrolidinyl-CO-morpholinyl,        -piperidinyl-CO-morpholinyl, —CH₂-piperidinyl-CO-morpholinyl,        -piperidinyl-CO-thiomorpholinyl,        -piperidinyl-CO-dihydroisoindole, -piperidinyl-CO-piperazinyl,        -piperidinyl-CO-pyrrolidinyl, -piperidinyl-CO-piperidinyl or        -piperidinyl-CO-dihydrobenzothiopyranyl) optionally substituted        by one or two ═O or R⁴ (eg. pyrazinyl) groups.

Most preferably, R² represents

-   -   —X-aryl (eg. -phenyl) optionally substituted by one or two        halogen (eg. fluorine), C₁₋₆ alkoxy (eg. methoxy), —CONR⁵R⁶ (eg.        —CON(H)(Me)), —NR⁵COR⁶ (eg. —NHCOMe) or cyano groups;    -   —X-aryl-Y-heterocyclyl (eg. -phenyl-pyrrolidinyl) optionally        substituted by one or two ═O or halogen (eg. fluorine) groups;    -   unsubstituted —X-heterocyclyl-Y-heterocyclyl (eg.        -piperidinyl-CO-morpholinyl);    -   —X-heteroaryl (eg. -2-pyridinyl or -2-pyrazinyl) optionally        substituted by a —CONR⁵R⁶ (eg. CON(H)(Me)) group; or    -   —X-heteroaryl-Y-heterocyclyl (eg. -2-pyridinyl-N-pyrrolidinyl)        wherein said heterocyclyl group is optionally substituted by an        ═O group (eg. -2-pyridinyl-N-pyrrolidinone).

Especially preferably, R² represents —X-heteroaryl (eg. -2-pyridinyl)substituted by a —CONR⁵R⁶ group (eg. 4-methylaminocarbonylpyridin-2-yl).

Preferably, n represents 0 or 1, more preferably 0.

When n represents 1, R³ is preferably a halogen (eg. iodine) atom or acyano group.

Preferred compounds according to the invention include examples E1-E288as shown below, or a pharmaceutically acceptable salt thereof.

More preferred compounds according to the invention include:

-   5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylic    acid methyl amide; and-   1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone    or a pharmaceutically acceptable salt thereof.

An especially preferred compound according to the invention is6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl-nicotinamideor a pharmaceutically acceptable salt thereof.

Compounds of formula (I) may form acid addition salts with acids, suchas conventional pharmaceutically acceptable acids, for example maleic,hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic,sulphate, citric, lactic, mandelic, tartaric and methanesulphonic.Salts, solvates and hydrates of compounds of formula (I) therefore forman aspect of the invention.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of these compounds and themixtures thereof including racemates. Tautomers also form an aspect ofthe invention.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises:

(a) reacting a compound of formula (II)

wherein R¹, R³ and n are as defined above, with a compound of formulaR^(2′)-L¹, wherein R^(2′) is as defined above for R² or a groupconvertible thereto and L¹ represents a suitable leaving group such as ahalogen atom (eg. bromine or iodine) or an optionally activated hydroxylgroup;(b) reacting a compound of formula (III)

wherein R², R³ and n are as defined above, with a compound of formulaR^(1′)-L², wherein R^(1′) is as defined above for R¹ or a groupconvertible thereto and L² represents a suitable leaving group such as ahalogen atom (eg. bromine, iodine or tosylate); or(c) reacting a compound of formula (III) as defined above, with a ketoneof formula R^(1′)═O, wherein R^(1′) is as defined above for R¹ or agroup convertible thereto; or(d) deprotecting a compound of formula (I) which is protected; and(e) interconversion to other compounds of formula (I).

When the leaving group L¹ is attached to an sp³ hybridised carbon, forexample, R^(2′)-L¹ is an alkyl halide, process (a) typically comprisesthe use of a suitable base, such as potassium carbonate in anappropriate solvent such as 2-butanone optionally in the presence of acatalyst such as potassium iodide at an appropriate temperature such asreflux.

When the leaving group L¹ is attached to an sp² hybridised carbon, forexample, R^(2′)-L¹ is an aryl halide, process (a) typically comprisesthe use of a copper(I) salt, such as copper (I) iodide, in the presenceof a base such as sodium hydride, in an appropriate solvent such aspyridine, at an appropriate temperature such as reflux.

When the leaving group L¹ is attached to an activated sp² hybridisedcarbon for example, R^(2′)-L¹ is a heteroaryl halide such as a2-chloropyridine or 2-chloropyrazine, process (a) typically comprisesthe use of a suitable base, such as sodium hydride in an appropriatesolvent such as dimethylformamide or dimethyl sulfoxide, at anappropriate temperature. Alternatively, potassium tert-butoxide intert-butanol at an appropriate temperature may also be employed.

When the leaving group L¹ is attached to an activated sp² hybridisedcarbon, for example R^(2′)-L¹ is an aryl halide such as3,4-difluoro-benzonitrile, process (a) typically comprises the use of asuitable base, potassium carbonate, in a suitable solvent, such asdimethyl sulfoxide, at a suitable temperature.

When L¹ is a hydroxyl group attached to an sp³ hybridised carbon, forexample, R^(2′)-L¹ is an alcohol, process (a) typically comprises theuse of a phosphine such as triphenylphosphine in a suitable solvent suchas tetrahydrofuran, followed by addition of an azodicarboxylate such asdiethylazodicarboxylate at a suitable temperature such as roomtemperature.

Process (b) typically comprises the use of a suitable base, such aspotassium carbonate in an appropriate solvent such as 2-butanoneoptionally in the presence of a catalyst such as potassium iodide at anappropriate temperature such as reflux.

Process (c) typically comprises the use of reductive conditions (such astreatment with a borohydride eg. sodium triacetoxyborohydride),optionally in the presence of an acid, such as acetic acid, in anappropriate solvent such as dichloromethane at a suitable temperaturesuch as room temperature.

In process (d), examples of protecting groups and the means for theirremoval can be found in T. W. Greene ‘Protective Groups in OrganicSynthesis’ (J. Wiley and Sons, 1991). Suitable amine protecting groupsinclude sulphonyl (e.g. tosyl), acyl (e.g. acetyl,2′,2′,2′-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl)and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.using an acid such as hydrochloric acid in dioxan or trifluoroaceticacid in dichloromethane) or reductively (e.g. hydrogenolysis of a benzylgroup or reductive removal of a 2′,2′,2′-trichloroethoxycarbonyl groupusing zinc in acetic acid) as appropriate. Other suitable amineprotecting groups include trifluoroacetyl (—COCF₃) which may be removedby base catalysed hydrolysis or a solid phase resin bound benzyl group,such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellmanlinker), which may be removed by acid catalysed hydrolysis, for examplewith trifluoroacetic acid.

Process (e) may be performed using conventional interconversionprocedures such as epimerisation, oxidation, reduction, alkylation,nucleophilic or electrophilic aromatic substitution, ester hydrolysis,amide bond formation or transition metal mediated coupling reactions.Examples of transition metal mediated coupling reactions useful asinterconversion procedures include the following: Palladium catalysedcoupling reactions between organic electrophiles, such as aryl halides,and organometallic reagents, for example boronic acids (Suzukicross-coupling reactions); Palladium catalysed amination and amidationreactions between organic electrophiles, such as aryl halides, andnucleophiles, such as amines and amides; Copper catalysed amidationreactions between organic electrophiles (such as aryl halides) andnucleophiles such as amides; and Copper mediated coupling reactionsbetween phenols and boronic acids.

Compounds of formula (II) and (III) may be prepared in accordance withthe following scheme

wherein R¹, R², R^(2′), R³, n and L¹ are as defined above and P¹represents a suitable protecting group such as Boc.

Step (i) typically comprises a deprotection reaction, for example, whenP¹ represents Boc the deprotection reaction comprises reaction of acompound of formula (IV) with an acid, for example hydrochloric acid indioxan or trifluoroacetic acid in dichloromethane.

Step (ii) may be performed under reducing conditions in an analogousmanner to that described for process (c).

Step (iii) may be performed in an analogous manner to that described forprocess (a).

Step (iv) typically comprises a deprotection reaction to provide acompound of formula (III) and can be performed as described in step (i).

Compounds of formula (VI) wherein R² represents —X-aryl, —X-heteroaryl,—X-aryl-Y—C₃₋₈ cycloalkyl, —X-aryl-Y-aryl, —X-aryl-Y-heteroaryl,—X-aryl-Y-heterocyclyl, —X-heteroaryl-Y—C₃₋₈ cycloalkyl,—X-heteroaryl-Y-aryl, —X-heteroaryl-Y-heteroaryl or—X-heteroaryl-Y-heterocyclyl and X represents a bond may also beprepared in accordance with the following scheme

wherein R², R^(2′), R³ and n are as defined above and P¹ represents asuitable protecting group such as Boc.

Step (i) may be performed under palladium catalysed cross-couplingconditions, for example usingbis(diphenylphosphino)ferrocenedichloropalladium (II) complex and1,1′-bis(diphenylphosphino)ferrocene as the catalyst system, incombination with a suitable base, such as potassium acetate, in asuitable solvent, for example dioxane, at a suitable temperature, forexample reflux.

Step (ii) may be performed under oxidising conditions, for example usingsodium periodate in the presence of ammonium acetate, in a suitablesolvent system, such as acetone and water, at a suitable temperature,for example room temperature.

Step (iii) may be performed in the presence of a copper salt, forexample copper acetate, in combination with a suitable base, such astriethylamine, together with molecular sieves, in a suitable solvent,for example dichloromethane, at a suitable temperature, for example roomtemperature.

Compounds of formula (IV) may be prepared in an analogous manner tothose described in Description 3 of WO 02/40471.

Compounds of formula (VII) may be prepared as outlined in Bioorg. Med.Chem. Lett.; 10; 22; 2000; 2553-2556.

Compounds of formula (I) and their pharmaceutically acceptable saltshave affinity for and are antagonists and/or inverse agonists of thehistamine H3 receptor and are believed to be of potential use in thetreatment of neurological diseases including Alzheimer's disease,dementia, age-related memory dysfunction, mild cognitive impairment,cognitive deficit, epilepsy, neuropathic pain, inflammatory pain,migraine, Parkinson's disease, multiple sclerosis, stroke and sleepdisorders including narcolepsy; psychiatric disorders includingschizophrenia (particularly cognitive deficit of schizophrenia),attention deficit hypereactivity disorder, depression and addiction; andother diseases including obesity, asthma, allergic rhinitis, nasalcongestion, chronic obstructive pulmonary disease and gastrointestinaldisorders.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance in the treatment or prophylaxis of the above disorders, inparticular cognitive impairments in diseases such as Alzheimer's diseaseand related neurodegenerative disorders.

The invention further provides a method of treatment or prophylaxis ofthe above disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment of the abovedisorders.

When used in therapy, the compounds of formula (I) are usuallyformulated in a standard pharmaceutical composition. Such compositionscan be prepared using standard procedures.

Thus, the present invention further provides a pharmaceuticalcomposition for use in the treatment of the above disorders whichcomprises the compound of formula (I) or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical compositionwhich comprises the compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

Compounds of formula (I) may be used in combination with othertherapeutic agents, for example histamine H1 antagonists or medicamentsclaimed to be useful as either disease modifying or symptomatictreatments of Alzheimer's disease. Suitable examples of such othertherapeutic agents may be agents known to modify cholinergictransmission such as 5-HT₆ antagonists, M1 muscarinic agonists, M2muscarinic antagonists or acetylcholinesterase inhibitors. When thecompounds are used in combination with other therapeutic agents, thecompounds may be administered either sequentially or simultaneously byany convenient route.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablederivative thereof together with a further therapeutic agent or agents.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilisation cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration. The dose of the compound used in the treatment of theaforementioned disorders will vary in the usual way with the seriousnessof the disorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 1.0 to 200 mg, and such unit doses may be administeredmore than once a day, for example two or three a day. Such therapy mayextend for a number of weeks or months.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

Description 17-Benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D1)

7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (790 mg, 3 mmol),potassium carbonate (1.24 g, 9 mmol) and catalytic potassium iodide weresuspended in 2-butanone (20 ml). Benzyl bromide (536 μL, 4.5 mmol) wasadded and the mixture heated at reflux for 24 hours. The solids werefiltered and then washed with acetone. The filtrate was concentrated invacuo and the crude oil purified by column chromatography, eluting witha mixture of ethyl acetate and hexane (1:4) to afford the title compound(D1) (1.06 g, 100%), ¹H NMR (CDCl₃) 7.44 (5H, m), 7.03 (1H, d, J=8.1Hz), 6.77 (1H, s), 6.74 (1H, dd, J 8.1 & 2.4 Hz), 3.49 (4H, m), 2.84(4H, m), 1.48 (9H, s).

Description 2 7-Benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine (D2)

7-Benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (D1) (1.06 g, 3 mmol) was dissolved in dichloromethane(15 ml) and treated with trifluoroacetic acid (15 ml). The solution wasstirred at room temperature for 2 hours, concentrated in vacuo and thentwice co-evaporating with dichloromethane. The residue was dissolved inmethanol and applied to a SCX ion exchange column (Varian bond-elute, 10g) and washed with methanol and then a mixture of 0.880ammonia/methanol. The combined basic fractions were reduced in vacuo andthe residue purified by column chromatography, eluting with a mixture of0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the titlecompound (D2) (702 mg, 93%), MS (ES+) m/e 254 [M+H]⁺.

Description 37-(4-Methoxycarbonyl-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D3)

7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (WO 02/40471) (5.27 g, 20.0 mmol), potassium carbonate(8.30 g, 60.0 mmol) and catalytic potassium iodide were suspended inbutanone (100 ml). Methyl 4-(bromomethyl)benzoate (5.5 g, 24.0 mmol)dissolved in butanone (50 ml) was added dropwise after which thereaction mixture was stirred at reflux for 24 hours. The reactionmixture was cooled, the solids were filtered and then washed withacetone. The filtrate was concentrated in vacuo and the crude mixturewas purified by column chromatography eluting with a mixture of ethylacetate:hexane (1:4) to afford the title compound (D3). MS (ES+) m/e 344[(M+H)—CO₂ ^(t)Bu]⁺.

Description 44-(2,3,4,5-Tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acidmethyl ester (D4)

7-(4-Methoxycarbonyl-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylicacid tert-butyl ester (D3) (6.35 g) was dissolved in dichloromethane (30ml) and treated with trifluoroacetic acid (30 ml). The solution wasstirred at room temperature for 2 hours, concentrated in vacuo and thentwice co-evaporated with dichloromethane. The residue was dissolved indichloromethane and washed with 10% aqueous sodium hydroxide, water andbrine. The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo to afford the title compound (D4).

Description 5 1-(6-Chloro-pyridin-3-yl)-1-morpholin-4-yl-methanone (D5)

Morpholine (0.2 ml, 2.2 mmol) was added to stirred solution of6-chloronicotinoyl chloride (250 mg, 1.4 mmol) in dichloromethane (10ml). After 2 hours the reaction was allowed to cool and the crudemixture was applied to a SCX ion exchange cartridge (Varian bond-elute,10 g) and washed with methanol. The methanolic fractions wereconcentrated in vacuo to afford the title compound (D5).

Descriptions 6-31

Descriptions 6-31 (D6-D31) were prepared and used without furthercharacterisation using the method described for Description 5 (D5) fromthe appropriate aryl halide and amine indicated in the table:

Description Aryl Halide Amine 1-(6-Chloro-pyridin-3-yl)-1-6-Chloronicotinoyl Pyrrolidine pyrrolidin-1-yl-methanone (D6) chloride6-Chloro-nicotinamide (D7) 6-Chloronicotinoyl Ammonia chloride6-Chloro-N,N-dimethyl- 6-Chloronicotinoyl Dimethylamine nicotinamide(D8) chloride 6-Chloro-N-ethyl-N-methyl- 6-ChloronicotinoylN-Ethylmethyl-amine nicotinamide (D9) chloride6-Chloro-N-methyl-nicotinamide 6-Chloronicotinoyl Methylamine (D10)chloride 6-Chloro-N-cyclopentyl- 6-Chloronicotinoyl Cyclopentylaminenicotinamide (D11) chloride 1-(6-Chloro-pyridin-3-yl)-1-6-Chloronicotinoyl Piperidine piperidin-1-yl-methanone (D12) chloride1-(2-Chloro-pyridin-4-yl)-1- 2-Chloro-isonicotinoyl Piperidinepiperidin-1-yl-methanone (D13) chloride 1-(2-Chloro-pyridin-4-yl)-1-2-Chloro-isonicotinoyl Pyrrolidine pyrrolidin-1-yl-methanone (D14)chloride 1-(2-Chloro-pyridin-4-yl)-1- 2-Chloro-isonicotinoyl Morpholinemorpholin-4-yl-methanone (D15) chloride 1-(6-Chloro-pyridin-2-yl)-1-6-Chloro-pyridine-2- Piperidine piperidin-1-yl-methanone (D16) carbonylchloride 1-(6-Chloro-pyridin-2-yl)-1-(1,1- 6-Chloro-pyridine-2-Thiomorpholine 1,1-dioxide dioxothiomorpholin-4-yl)- carbonyl chloridemethanone (D17) 1-(6-Chloro-pyridin-2-yl)-1- 6-Chloro-pyridine-2-Pyrrolidine pyrrolidin-1-yl-methanone (D18) carbonyl chloride1-(6-Chloro-pyridin-2-yl)-1- 6-Chloro-pyridine-2- Morpholinemorpholin-4-yl-methanone (D19) carbonyl chloride1-(2-Chloro-pyridin-3-yl)-1- 2-Chloro-nicotinoyl Morpholinemorpholin-4-yl-methanone (D20) chloride 1-(2-Chloro-pyridin-3-yl)-1-2-Chloro-nicotinoyl Piperidine piperidin-1-yl-methanone (D21) chloride1-(4-Iodo-phenyl)-1-morpholin-4- 4-Iodo-benzoyl chloride Morpholineyl-methanone (D22) 4-Iodo-N-cyclopropylmethyl- 4-Iodo-benzoyl chlorideCyclopropylmethyl-amine benzamide (D23)1-(4-Iodo-phenyl)-1-pyrrolidin-1- 4-Iodo-benzoyl chloride Pyrrolidineyl-methanone (D24) 4-Iodo-N-cyclobutyl-benzamide 4-Iodo-benzoyl chlorideCyclobutylamine (D25) 4-Iodo-N,N-diethyl-benzamide 4-Iodo-benzoylchloride Diethylamine (D26) 4-Iodo-N-(2-cyano-ethyl)-N- 4-Iodo-benzoylchloride 3-Methylamino-propionitrile methyl-benzamide (D27)1-(3-Iodo-phenyl)-1-morpholin-4- 3-Iodo-benzoyl chloride Morpholineyl-methanone (D28) 3-Iodo-N-cyclopropylmethyl- 3-Iodo-benzoyl chlorideCyclopropylmethyl-amine benzamide (D29) 4-(4-Iodo-benzenesulfonyl)-4-Iodo-benzenesulfonyl Morpholine morpholine (D30) chloride4-Iodo-N,N-diethyl- 4-Iodo-benzenesulfonyl Diethylaminebenzenesulfonamide (D31) chloride

Description 32 5-Bromo-2-(1-piperidinyl)pyrimidine (D32)

Piperidine (5.1 ml, 51.6 mmol) was added to a stirred solution of5-bromo-2-chloropyrimidine (5 g, 25.8 mmol) and triethylamine (9.0 ml,64.5 mmol) in toluene (30 ml). After stirring at room temperature for 24hours the reaction mixture was diluted with ethyl acetate and washedwith 2N hydrochloric acid, brine and dried (magnesium sulfate). Theorganic layer was filtered, concentrated in vacuo and the resultingresidue was purified by column chromatography eluting with ethyl acetateto afford the title compound (D32).

Descriptions 33-35

Descriptions 33-35 (D33-D35) were prepared using an analogous method tothat described for Description 32 (D32) substituting piperidine for theappropriate amine indicated in the table:

Description Amine 5-Bromo-2-(1-pyrrolidinyl)pyrimidine (D33) Pyrrolidine4-(5-Bromo-2-pyrimidinyl)thiomorpholine 1,1- Thiomorpholine 1,1- dioxide(D34) dioxide 5-Bromo-N-methyl-2-pyrimidinamine (D35) Methylamine

Descriptions 36-37

Descriptions 36-37 (D36-D37) were prepared using an analogous method tothat described for Description 5 (D5), substituting morpholine for theappropriate amine indicated in the table:

Description Amine 6-Chloro-N-(cyclopropylmethyl)-3-Cyclopropylmethylamine pyridinecarboxamide (D36)5-(1-Azetidinylcarbonyl)-2-chloropyridine Azetidine (D37)

Description 38 5-Bromo-2-pyrimidinecarbonitrile (D38)

Sodium cyanide (2.30 g, 46.6 mmol) was dissolved in dimethylformamide(60 ml) and treated with 5-bromo-2-chloropyrimidine (6.0 g, 31.1 mmol).The resulting mixture was stirred at room temperature for 18 hours,diluted with water and extracted with dichloromethane. Thedichloromethane extracts were combined, washed with water, dried(magnesium sulphate), filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography eluting with a mixture ofethyl acetate:hexane (1:4) to afford the title compound (D38).

Description 39 1,1-Dimethylethyl7-({5-[(methylamino)carbonyl]-2-pyridinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(D39)

7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (8.7 g, 33 mmol)was dissolved in tert-butanol and treated with potassium-tert-butoxide(4 g, 36 mmol). After stirring for 30 minutes at room temperature,6-chloro-N-methyl-nicotinamide (D10) (5.1 g, 30 mmol) was added and thereaction mixture was stirred at reflux for 20 hours. The reactionmixture was cooled to room temperature and concentrated in vacuo.Ice/water was added to the crude residue resulting in a precipitatewhich was collected by filtration. The solid precipitate was dissolvedin ethyl acetate, washed with brine and dried (magnesium sulfate). Theorganic layer was filtered, concentrated in vacuo and the resultingresidue was purified by column chromatography eluting with a mixture ofethyl acetate:hexane (1:1) to afford the title compound (D39). NMR(CDCl₃) 8.52 (1H, d, J=

2.4), 8.12 (1H, dd, J=8.8), 7.16 (1H, m), 6.95-6.81 (3H, m), 6.02 (1H,br), 3.57 (4H, br), 3.02

(3H, d, J=2.4), 2.89 (4H, br), 1.49 (9H, s).

Description 40N-Methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide(D40)

1,1-Dimethylethyl7-({5-[(methylamino)carbonyl]-2-pyridinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(D39) (3.98 g, 10 mmol) was dissolved in dioxane (40 ml) and treatedwith a solution of 4M hydrogen chloride in dioxane (35 ml). The reactionmixture was allowed to stir at room temperature for 6 hours and thenconcentrated in vacuo to afford the title compound (D40); MS (ES+) m/e298 [M+H]⁺.

Description 41 1,1-Dimethylethyl7-hydroxy-8-iodo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D41)

A solution of7-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylic acidtert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (5.2 g, 20 mmol)in 33% methylamine in ethanol (30 ml) was stirred at 0° C. A solution ofsodium iodide (4.6 g, 30 mmol) and iodine (5.2 g, 20 mmol) in water (30ml) was added below the surface of the reaction mixture. After stirringat 0° C. for 1 hour the mixture was concentrated in vacuo. The residuewas diluted with ethyl acetate and water. The organic layer wasseparated, washed with water and brine. The organic layer was dried overmagnesium sulfate, filtered and concentrated in vacuo to afford thetitle compound (D41); (7.0 g, 90%), ¹H NMR (d₆-DMSO) 10.0 (1H, br s),7.41 (1H, s), 6.65 (1H, s), 3.40 (4H, m), 2.70 (4H, m), 1.40 (9H, s).

Description 42 1,1-Dimethylethyl7-iodo-8-({5-[(methylamino)carbonyl]-2-pyridinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(D42)

Sodium hydride (60% disp. in mineral oil, 240 mg, 6 mmol) was added to astirred solution of 1,1-dimethylethyl7-hydroxy-8-iodo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D41)(1.94 g, 5 mmol) in dimethyl sulfoxide (10 ml). After 10 minutes,6-chloro-N-methyl-nicotinamide (D10) (850 mg, 5 mmol) was added and thereaction mixture was heated to 100° C. for 20 hours. After cooling toroom temperature the reaction mixture was diluted with water anddichloromethane. The organic layer was separated, washed with water andbrine, dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by column chromatography (1:1 ethylacetate:hexanes) to afford the title product (D42).

Description 43N-Methyl-6-(8-iodo-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide(D43)

Description 43 (D43) was prepared from 1,1-dimethylethyl7-iodo-8-({5-[(methylamino)carbonyl]-2-pyridinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(D42) using an analogous method to that described for Description 2(D2); MS (ES+) m/e 424 [M+H]⁺.

Description 44 1,1-Dimethylethyl 7-iodo-8-[(phenylmethyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D44)

Sodium hydride (60% disp. in mineral oil, 576 mg, 14.4 mmol) was addedto a stirred solution of 1,1-dimethylethyl7-hydroxy-8-iodo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D41)(4.67 g, 12 mmol) in dimethylformamide (30 ml). After 15 minutes, benzylbromide (2.04 g, 1.4 ml, 12 mmol) was added and the mixture stirred for2 hours. The mixture was diluted with water and ethyl acetate, theorganic layer was separated, washed with water and brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography eluting with a mixture of ethylacetate:hexanes (1:10) to afford the title product (D44).

Description 457-Iodo-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (D45)

Description D45 (D45) was prepared from 1,1-dimethylethyl7-iodo-8-[(phenylmethyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(D44) using the analogous method to that described for Description 2(D2); MS (ES+) m/e 380 [M+H]⁺.

Description 46 1-(3-Chloro-2-pyrazinyl)-2-pyrrolidinone (D46)

Step 1: 3-Chloropyrazine 1-oxide

A mixture of chloropyrazine (9.6 g, 83.3 mmol) and hydrogen peroxidesolution (30%, 16 ml) in glacial acetic acid (26 ml) was heated at 70°C. for 18 hours. The mixture was allowed to cool to room temperature,poured into water (250 ml) and extracted with dichloromethane (3×100ml). The dichloromethane extracts were combined, washed with saturatedsodium bicarbonate solution (2×70 ml), water (3×100 ml) and brine (100ml). The organic portion was dried under sodium sulfate and evaporatedin vacuo to give a white solid which was recrystallised from absoluteethanol to give the title compound (0.45 g). ¹H NMR (CDCl₃) 8.27-8.26(1H, d), 8.15 (1H, s), 8.03-8.02 (1H, dd).

Step 2: 2,3-Dichloropyrazine

3-Chloropyrazine 1-oxide (D46, Step 1) (2.2 g, 16.9 mmol) was addedslowly to phosphorus oxychloride (10 ml) at 60° C. When the addition wascomplete the mixture was heated at reflux for 60 minutes. The mixturewas allowed to cool and poured into ice and solid sodium acetate (5 g).This was stirred until the ice had melted and then extracted withdichloromethane. The dichloromethane extracts were combined, washed withsaturated sodium bicarbonate solution, water and brine. The organicportion was dried under sodium sulfate and evaporated in vacuo. Theresulting residue was purified by column chromatography eluting with amixture of ethyl acetate:hexane (1:20) to afford the title compound(0.86 g). ¹H NMR (CDCl₃) 8.32 (2H, s).

Step 3: 1-(3-Chloro-2-pyrazinyl)-2-pyrrolidinone

Sodium hydride (60% in mineral oil, 67 mg, 1.62 mmol) was added to asolution of pyrrolidinone (0.12 ml, 1.54 mmol) in dry dimethylformamide(5 ml) under argon at 0° C. The mixture was allowed to warm to roomtemperature over 1.5 hours. A solution of 2,3-dichloropyrazine (D46,Step 2) (250 mg, 1.69 mmol) in dry dimethylformamide (2 ml) was addedand the mixture stirred at room temperature under argon for 2 hours. Themixture was poured onto water (30 ml) and was extracted with ethylacetate (×3). The ethyl acetate extracts were combined, washed withbrine, dried under magnesium sulfate and evaporated in vacuo. Theresulting residue was purified by column chromatography eluting with amixture of ethyl acetate:pentane (1:1) to afford the title compound(0.10 g); MS (ES+) m/e 198 [M+H]⁺.

Description 47 2,5-Dichloropyrazine (D47)

Step 1: 5-Chloro-2-pyrazinamine

Aminopyrazine (10 g, 10.5 mmol) was dissolved in dry dimethylformamide(60 ml) and was treated with N-chlorosuccinimide (15.36 g, 11.5 mmol)under argon at 0° C. The mixture was stirred for 30 minutes and thenallowed to warm to room temperature. The mixture was poured onto waterand extracted with diethyl ether. The diethyl ether layers were combinedand evaporated in vacuo. The resulting residue was purified by columnchromatography eluting with a mixture of ethyl acetate:pentane (1:9) toafford the title compound (1.40 g); ¹H NMR (CDCl₃) 8.02 (1H, s), 7.76(1H, s), 4.61 (2H, s).

Step 2: 2,5-Dichloropyrazine

5-Chloro-2-pyrazinamine (D47, Step 1) (2.41 g, 18.6 mmol) was dissolvedin concentrated hydrochloric acid (24 ml), cooled in an ice-acetone bathand treated with a solution of sodium nitrite (2.63 g, 38.1 mmol) inwater (18 ml) dropwise over a period of 1 hour. The mixture was cooledin an ice-water bath and left to stir for 1 hour. The mixture wasallowed to warm to room temperature over 1 hour, neutralised by additionof sodium hydroxide solution (2M) and extracted with dichloromethane.The dichloromethane layers were combined, dried under magnesium sulfateand evaporated in vacuo. The resulting residue was purified by columnchromatography eluting with a mixture of ethyl acetate:pentane (1:9) toafford the title compound (0.33 g); ¹H NMR (CDCl₃) 8.40 (2H, s).

Description 48 2,5-Dibromopyrazine (D48)

Step 1: 5-Bromo-2-pyrazinamine

Aminopyrazine (5.0 g, 52.6 mmol) was dissolved in chloroform (150 ml)and pyridine (5.11 ml, 63.2 mmol) was added. A solution of bromine (3.24ml, 63.2 mmol) in chloroform (50 ml) was added dropwise over 1 hour. Themixture was allowed to stir for 30 minutes, diluted with water (50 ml)and allowed to stir for 10 minutes. The organic layer was separated,washed with water (50 ml), dried under magnesium sulfate and evaporatedin vacuo. The resulting residue was purified by column chromatographyeluting with a mixture of ethyl acetate:pentane (1:4) to afford thetitle compound (0.32 g); MS (ES+) m/e 175 [M+H]⁺.

Step 2: 2,5-Dibromopyrazine

5-Bromo-2-pyrazinamine (D48, Step 1) (317 mg, 1.82 mmol) was added to acooled (ice-acetone bath) solution of hydrobromic acid (48% aqueous) (2ml). After stirring for 5 minutes, bromine (0.28 ml, 5.46 mmol) wasadded followed by a solution of sodium nitrite (314 mg, 4.55 mmol) inwater dropwise over 15 minutes. The mixture was stirred for 30 minutesand allowed to warm to room temperature over 30 minutes. A solution ofsodium hydroxide (2.6 g) in water (7 ml) was added and the mixturestirred for 1 hour. The mixture was extracted with dichloromethane. Thedichloromethane layers were combined and evaporated in vacuo to affordthe title compound (60 mg). ¹H NMR (CDCl₃) 8.49 (2H, s).

Description 49N-Methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide(D49)

Step 1: 1,1-Dimethylethyl7-({5-[(methyloxy)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

Sodium hydride (60% dispersion in mineral oil) (6.4 g, 0.16 mol) wasadded portionwise to a solution of7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (40 g, 0.15 mol)in dry dimethylformamide (200 ml) cooled to 5° C. over 15 minutes. After15 minutes, the mixture was allowed to warm to room temperature andstirred for 60 minutes. The mixture was cooled in an ice-water bath andmethyl 5-chloro-2-pyrazinecarboxylate (31.2 g, 0.18 mol) was addedportionwise. The mixture was allowed to warm to room temperature andstirred for 18 hours. The mixture was poured onto water (500 ml) and ice(500 ml) and stirred until the ice had melted. The resulting solid wascollected by filtration, washed with water and dissolved in ethylacetate (1500 ml). The ethyl acetate layer was washed with brine (200ml), dried under sodium sulfate and evaporated in vacuo. The crudeproduct was purified by column chromatography eluting with a mixture ofethyl acetate:hexane (1:2) to afford the title compound (35.07 g).

Step 2:5-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxylicacid

2M Sodium hydroxide solution (110 ml) was added to a solution of1,1-dimethylethyl7-({5-[(methyloxy)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(D49, Step 1) (29.38 g, 73.6 mmol) in acetone (480 ml) and the resultingmixture was stirred at room temperature for 25 minutes. The mixture wasacidified with 2M hydrochloric acid and then poured into water (2 L).The resulting white solid was collected by filtration, washed with waterand dissolved in ethyl acetate (1 L). This solution was dried undersodium sulfate and evaporated in vacuo to give the title compound (27.3g); MS (ES+) m/e 384 [M−H]⁺.

Step 3: 1,1-Dimethylethyl7-({5-[(methylamino)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

1,1′-Carbonyldiimidazole (16.6 g, 102 mmol) was added to a solution of5-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxylicacid (D49, Step 2) (37.5 g, 97 mmol) in dry dichloromethane (400 ml) andthe resulting mixture was stirred at room temperature for 18 hours.Methylamine (2M solution in tetrahydrofuran) (100 ml) was added and themixture stirred for 2 hours. The solvent was removed in vacuo and theresidue was purified by column chromatography eluting with a mixture ofethyl acetate:chloroform (1:1) to afford the title compound (25.8 g); MS(ES+) m/e 399 [M+H]⁺.

Step 4:N-Methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide

A solution of 1,1-dimethylethyl7-({5-[(methylamino)carbonyl]-2-pyrazinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(D49, Step 3) (44.26 g, 0.11 mol) in dichloromethane (800 ml) was addeddropwise to a stirring solution of 4M hydrogen chloride in dioxane (270ml, 1.1 mol). The resulting mixture was stirred at room temperature for60 minutes. A further quantity of 4M hydrogen chloride in dioxane (30ml, 0.12 mol) was added and the mixture stirred for 60 minutes. Theresulting white solid was collected by filtration and washed withdichloromethane. The solid was dissolved in water (2 L) and basified byaddition of saturated sodium carbonate solution. The water layer wasextracted with dichloromethane and the extracts filtered through celite.The celite was washed with methanol and the combined dichloromethane andmethanol washings were evaporated in vacuo to give the title compound(25.1 g); MS (ES+) m/e 299 [M+H]⁺.

Descriptions 50-52

Descriptions 50-52 (D50-D52) were prepared and used without furthercharacterisation using the method described for Description 5 (D5) fromthe appropriate aryl halide and amine indicated in the table:

Description Aryl Halide Amine N-Ethyl-4-iodo-N-[2- 4-Iodobenzoylchloride 2-Methoxyethyl (methyloxy)ethyl]benzamide (D50) ethylamine4-Iodo-N-methylbenzamide (D51) 4-Iodobenzoyl chloride Methylamine1-[(3-Iodophenyl)carbonyl]pyrrolidine (D52) 3-Iodobenzoyl chloridePyrrolidine

Description 53(2E)-1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-3-(dimethylamino)-2-propen-1-one(D53)

A mixture of1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}ethanone(E214) (186 mg, 0.55 mmol), dimethylformamide dimethyl acetyl (0.25 ml)and xylene (4 ml) was heated at reflux for 8 hours. The residue wasdiluted with toluene and concentrated in vacuo to afford the titlecompound (D53); MS (ES+) m/e 392 [M+H]⁺.

Description 546-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarbohydrazide(D54)

A mixture of thionyl chloride (2 ml) and6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxylicacid (E196b) (200 mg, 0.59 mmol) was stirred at reflux for 1 hour. Thereaction mixture was concentrated in vacuo to afford a crude residue.The residue was dissolved in tetrahydrofuran (5 ml), cooled to 0° C. andhydrazine hydrate (1.5 ml) in tetrahydrofuran (1.5 ml) was addeddropwise. The reaction mixture was allowed to warm to room temperatureand stirred for 1 hour. The reaction mixture was then diluted with ethylacetate and washed with a saturated solution of sodium carbonate, water,brine and dried (magnesium sulfate). The organic layer was filtered andconcentrated in vacuo to afford the title compound (D54); MS (ES+) m/e361 [M+H]⁺.

Description 55 cis-4-(4-Morpholinylcarbonyl)cyclohexanol (D55)

A solution of cis-4-hydroxycyclohexanecarboxylic acid (720 mg, 0.5mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (1.33g, 6 mmol) and 1-hydroxy-7-azabenzotriazole (816 mg, 6 mmol) indichloromethane (6 ml) was treated with morpholine 1.3 ml, 15 mmol).After stirring at room temperature for 18 hours, the crude reaction wasapplied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) andwashed with methanol and then a mixture of 0.880 ammonia:methanol (1:9).The combined basic fractions were concentrated in vacuo, and theresulting residue was purified by column chromatography eluting with amixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford thetitle compound (D55); MS (ES+) m/e 214 [M+H]⁺.

Description 56 2-Chloro-6-[4-(methylsulfonyl)phenyl]pyrazine (D56)

2,6-Dichloropyrazine (2.98 g, 20.0 mmol),[4-(methylsulfonyl)phenyl]boronic acid (2 g, 10.0 mmol),tetrakis(triphenylphospine)palladium (1.15 g, 1.0 mmol), potassiumphosphate (10.2 g, 48 mmol) and dimethylformamide (90 ml) were heated to80° C. for 16 hours. The solvent was removed in vacuo and the productwas dissolved in chloroform and filtered through celite. The filtratewas washed with water then separated. The residue was purified by columnchromatography eluting with a mixture of ethylacetate:hexane (4:6) toafford the title compound. MS (ES+) m/e 270 [M+H]⁺.

Example 1 7-Benzyloxy-3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E1)

7-Benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine (D2) (25.3 g, 100 mmol)was dissolved in 2.5% acetic acid in dichloromethane (400 ml) at 0° C.and treated dropwise with cyclobutanone (11.2 ml, 150 mmol). The mixturewas stirred for 30 minutes and then sodium triacetoxyborohydride (31.8g, 150 mmol) was added portion wise. The reaction mixture was stirred atroom temperature for 4 hours, basified with saturated sodium carbonatesolution and extracted with dichloromethane. The combined extracts werewashed with water, brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The crude residue was triturated with hexane andfiltered to afford the title product (E1). MS (ES+) m/e 308 [M+H]⁺.

Example 27-Benzyloxy-3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E2)

Title compound (E2) was prepared from7-benzyloxy-1,2,4,5-tetrahydro-benzo[d]azepine (D2) and cyclopentanoneusing the method described for Example 1; MS (ES+) m/e 322 [M+H]⁺.

Example 3 3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3)

7-Benzyloxy-3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E1)(9.22 g, 30 mmol) was dissolved in ethanol (150 ml) and tetrahydrofuran(50 ml). Palladium (1.5 g, 10% on charcoal paste) was added and thereaction mixture was stirred at room temperature under hydrogen (1atmosphere) for 5 hours. The reaction mixture was filtered throughcelite and the filtrate concentrated in vacuo. The crude residue wastriturated with diethyl ether and filtered to afford the title product(E3); MS (ES+) m/e 218 [M+H]⁺.

Example 4 3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E4)

Title compound (E4) was prepared from7-benzyloxy-3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E2)using the method described for Example 3 (E3); ¹H NMR (DMSO, d6) 9.08(1H, brs), 6.70 (1H, d), 6.53-6.47 (2H, m), 3.31-2.50 (9H, m) 1.88-1.43(8H, m).

Example 5a4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylicacid-tert-butyl ester (E5a)

3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E4) (1.1 g, 4.8mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.15 g,5.7 mmol), di-tert-butyl azodicarboxylate (1.31 g, 5.7 mmol) andtriphenylphosphine (1.5 g, 5.7 mmol) were stirred at room temperaturefor 16 hours in tetrahydrofuran (20 ml). The mixture was acidified withacetic acid and applied to a SCX ion exchange cartridge (Varianbond-elute, 10 g) and washed with methanol and then a mixture of 0.880ammonia:methanol (1:9). The combined basic fractions were concentratedin vacuo and the resulting residue was purified by column chromatographyeluting with a mixture of 0.880 ammonia:methanol:dichloromethane(1:9:90) to afford the title product (E5a); MS (ES+) m/e 415 [M+H]⁺.

Example 53-Cyclopentyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E5)

4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylicacid-tert-butyl ester (E5a) (593 mg, 1.43 mmol) was dissolved indichloromethane (5 ml) and treated with trifluoroacetic acid (3 ml). Thesolution was stirred at room temperature for 1 hour, concentrated invacuo and applied to a SCX ion exchange cartridge (Varian bond-elute, 5g) and washed with methanol and then a mixture of 0.880 ammonia:methanol(1:9). The combined basic fractions were concentrated in vacuo and theresulting residue was purified by column chromatography eluting with amixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford thetitle product (E5). MS (ES+) m/e 315 [M+H]⁺.

Examples 6-12

Examples 6-12 (E6-12) were prepared from either3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) or3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E4) and theappropriate alcohol indicated in the table using an analogous method tothat described for Example 5a (E5a) followed by the method described forthe preparation of Example 5 (E5).

Starting Example Material Alcohol LC/MS (M + H⁺⁾3-Cyclobutyl-7-(piperidin-4- E3 4-Hydroxy-piperidine-1- 301yloxy)-2,3,4,5-tetrahydro-1H- carboxylic acid tert-butyl benzo[d]azepine(E6) ester 3-Cyclobutyl-7-(piperidin-4- E3 4-Hydroxymethyl- 315ylmethoxy)-2,3,4,5- piperidine-1-carboxylic tetrahydro-1H- acidtert-butyl ester benzo[d]azepine (E7) 3-Cyclobutyl-7-((R)-1- E3(R)-2-Hydroxymethyl- 301 pyrrolidin-2-ylmethoxy)-pyrrolidine-1-carboxylic 2,3,4,5-tetrahydro-1H- acid tert-butyl esterbenzo[d]azepine (E8) 3-Cyclobutyl-7-((R)- E3 (R)-3-Hydroxy- 287pyrrolidin-3-yloxy)-2,3,4,5- pyrrolidine-1-carboxylic tetrahydro-1H-acid tert-butyl ester benzo[d]azepine (E9) 3-Cyclobutyl-7-((S)- E3(S)-3-Hydroxy- 287 pyrrolidin-3-yloxy)-2,3,4,5- pyrrolidine-1-carboxylictetrahydro-1H- acid tert-butyl ester benzo[d]azepine (E10)3-Cyclobutyl-7-((S)-1- E3 (S)-2-Hydroxymethyl- 301pyrrolidin-2-ylmethoxy)- pyrrolidine-1-carboxylic 2,3,4,5-tetrahydro-1H-acid tert-butyl ester benzo[d]azepine (E11)3-Cyclopentyl-7-(piperidin-4- E4 4-Hydroxymethyl- 329ylmethoxy)-2,3,4,5- piperidine-1-carboxylic tetrahydro-1H- acidtert-butyl ester benzo[d]azepine (E12)

Example 134-{1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-methanoyl}-benzonitrile(E13)

4-Cyanobenzoic acid (147 mg, 1 mmol), 1-hydroxy benzotriazole hydrate(154 mg, 1 mmol) and N-cyclohexylcarbodiimide N′-methyl polystyrene (1.8mmol/g, 555 mg, 1 mmol) were stirred at room temperature indichloromethane (5 ml) for 15 minutes.3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) (150 mg, 0.5 mmol) was added and stirring continued for 16 hours.The reaction mixture was applied to a SCX ion exchange cartridge (Varianbond-elute, 5 g) and washed with methanol and then a mixture of 0.880ammonia:methanol (1:9). The combined basic fractions were concentratedin vacuo and the resulting residue was purified by column chromatographyeluting with dichloromethane then a mixture of 0.880ammonia:ethanol:dichloromethate (1:9:90) to afford the title product(E13). MS (ES+) m/e 430 [M+H]⁺.

Examples 14-42

Examples 14-42 (E14-E42) were prepared using an analogous method to thatdescribed for Example 13 (E13) from the appropriate amine and acid asindicated in the table:

LC/MS Example Amine Acid (M + H⁺⁾ 1-[4-(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7- Tetrahydro-pyran- 413 tetrahydro-1H-benzo[d]azepin-7-(piperidin-4-yloxy)- 4-carboxylic acidyloxy)-piperidin-1-yl]-1-(tetrahydro- 2,3,4,5-tetrahydro-pyran-4-yl)-methanone (E14) 1H-benzo[d]azepine (E6)1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- Cyclohexane 411tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- carboxylic acidyloxy)-piperidin-1-yl]-1-cyclohexyl- 2,3,4,5-tetrahydro- methanone (E15)1H-benzo[d]azepine (E6) 1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-Isoquinoline-1- 456 tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)-carboxylic acid yloxy)-piperidin-1-yl]-1-isoquinolin-2,3,4,5-tetrahydro- 1-yl-methanone (E16) 1H-benzo[d]azepine (E6)4-{(E)-3-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- (E)-3-(4-Cyano- 456tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- phenyl)-acrylicyloxy)-piperidin-1-yl]-3-oxo- 2,3,4,5-tetrahydro- acidpropenyl}-benzonitrile (E17) 1H-benzo[d]azepine (E6)1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- Isoquinoline-6- 456tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- carboxylic acidyloxy)-piperidin-1-yl]-1-isoquinolin- 2,3,4,5-tetrahydro- 6-yl-methanone(E18) 1H-benzo[d]azepine (E6) 1-[4-(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7- 5-Methyl- 410 tetrahydro-1H-benzo[d]azepin-7-(piperidin-4-yloxy)- isoxazole-3- yloxy)-piperidin-1-yl]-1-(5-methyl-2,3,4,5-tetrahydro- carboxylic acid isoxazol-3-yl)-methanone (E19)1H-benzo[d]azepine (E6) 1-Benzothiazol-6-yl-1-[4-(3- 3-Cyclobutyl-7-Benzothiazole-6- 462 cyclobutyl-2,3,4,5-tetrahydro-1H-(piperidin-4-yloxy)- carboxylic acid benzo[d]azepin-7-yloxy)-piperidin-2,3,4,5-tetrahydro- 1-yl]-methanone (E20) 1H-benzo[d]azepine (E6)1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- Isonicotinic acid 406tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)-yloxy)-piperidin-1-yl]-1-pyridin-4-yl- 2,3,4,5-tetrahydro- methanone(E21) 1H-benzo[d]azepine (E6) 1-[4-(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7- 4-(1-Pyrrolidin-1- 502 tetrahydro-1H-benzo[d]azepin-7-(piperidin-4-yloxy)- yl-methanoyl)- yloxy)-piperidin-1-yl]-1-[4-(1-2,3,4,5-tetrahydro- benzoic acid pyrrolidin-1-yl-methanoyl)-phenyl]-1H-benzo[d]azepine (WO 03/04468) methanone (E22) (E6)1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- Thiophene-3- 411tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- carboxylic acidyloxy)-piperidin-1-yl]-1-thiophen-3- 2,3,4,5-tetrahydro- yl-methanone(E23) 1H-benzo[d]azepine (E6) 1-[4-(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7- Furan-3-carboxylic 395 tetrahydro-1H-benzo[d]azepin-7-(piperidin-4-yloxy)- acid yloxy)-piperidin-1-yl]-1-furan-3-yl-2,3,4,5-tetrahydro- methanone (E24) 1H-benzo[d]azepine (E6)1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- Tetrahydro-pyran- 427tetrahydro-1H-benzo[d]azepin-7- (piperidin-4- 4-carboxylic acidyloxymethyl)-piperidin-1-yl]-1- ylmethoxy)-2,3,4,5-tetrahydro-pyran-4-yl)-methanone tetrahydro-1H- (E25) benzo[d]azepine(E7) 1-[(R)-2-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((R)-Tetrahydro-pyran- 413 tetrahydro-1H-benzo[d]azepin-7- 1-pyrrolidin-2-4-carboxylic acid yloxymethyl)-pyrrolidin-1-yl]-1- ylmethoxy)-2,3,4,5-(tetrahydro-pyran-4-yl)-methanone tetrahydro-1H- (E26) benzo[d]azepine(E8) 1-[(R)-3-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((R)-Tetrahydro-pyran- 399 tetrahydro-1H-benzo[d]azepin-7-pyrrolidin-3-yloxy)- 4-carboxylic acid yloxy)-pyrrolidin-1-yl]-1-2,3,4,5-tetrahydro- (tetrahydro-pyran-4-yl)-methanone 1H-benzo[d]azepine(E27) (E9) 1-[(S)-3-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((S)-Tetrahydro-pyran- 399 tetrahydro-1H-benzo[d]azepin-7-pyrrolidin-3-yloxy)- 4-carboxylic acid yloxy)-pyrrolidin-1-yl]-1-2,3,4,5-tetrahydro- (tetrahydro-pyran-4-yl)-methanone 1H-benzo[d]azepine(E28) (E10) 1-[(S)-2-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((S)-1-Tetrahydro-pyran- 413 tetrahydro-1H-benzo[d]azepin-7- pyrrolidin-2-4-carboxylic acid yloxy)-pyrrolidin-1-yl]-1- ylmethoxy)-2,3,4,5-(tetrahydro-pyran-4-yl)-methanone tetrahydro-1H- (E29) benzo[d]azepine(E11) 1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- 4- 483tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- Methanesulfonyl-yloxy)-piperidin-1-yl]-1- 2,3,4,5-tetrahydro- benzoic acid(methanesulfonyl-phenyl)- 1H-benzo[d]azepine methanone (E30) (E6)1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- 2-Pyrazine 407tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- carboxylic acidyloxy)-piperidin-1-yl]-1-pyrazin-2- 2,3,4,5-tetrahydro- yl-methanone(E31) 1H-benzo[d]azepine (E6) 5-{1-[4-(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7- 6-Hydroxy 422 tetrahydro-1H-benzo[d]azepin-7-(piperidin-4-yloxy)- nicotinic acid yloxy)-piperidin-1-yl]-methanoyl}-2,3,4,5-tetrahydro- 1H-pyridone (E32) 1H-benzo[d]azepine (E6)1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- 2,3-Dihydro- 447tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- benzofuran-5-yloxy)-piperidin-1-yl]-1-(2,3- 2,3,4,5-tetrahydro- carboxylic aciddihydro-benzofuran-5-yl)- 1H-benzo[d]azepine methanone (E33) (E6)1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- 3-Methoxy- 387tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- propionic acidyloxy)-piperidin-1-yl]-3-methoxy- 2,3,4,5-tetrahydro- propan-1-one (E34)1H-benzo[d]azepine (E6) 1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-2,3-Dihydro- 447 tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)-benzofuran-7- yloxy)-piperidin-1-yl]-(2,3-dihydro- 2,3,4,5-tetrahydro-carboxylic acid benzofuran-7-yl)-methanone (E35) 1H-benzo[d]azepine (E6)4-{1-{4-(3-Cyclopentyl-7-(piperidin- 3-Cyclopentyl-7- 4-Cyano-benzoic458 4-ylmethoxy)-2,3,4,5-tetrahydro- (piperidin-4- acid1H-benzo[d]azepin-7- ylmethoxy)-2,3,4,5- yloxymethyl)piperidin-1-yl]-tetrahydro-1H- methanoyl}-benzonitrile (E36) benzo[d]azepine (E12)1-[4-(3-Cyclopentyl-2,3,4,5- 3-Cyclopentyl-7- 4-(1-Pyrrolidin-1- 530tetrahydro-1H-benzo[d]azepin-7- (piperidin-4- yl-methanoyl)-yloxymethyl)-piperidin-1-yl]-1-[4- ylmethoxy)-2,3,4,5- benzoic acid (WO(1-pyrrolidin-1-yl-methanoyl)- tetrahydro-1H- 03/04468A1)phenyl]-methanone (E37) benzo[d]azepine (E12)4-{1-[4-(3-Cyclopentyl-2,3,4,5- 3-Cyclopentyl-7- 4-Cyano-benzoic 444tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- acidyloxy)-piperidin-1-yl]-methanoyl}- 2,3,4,5-tetrahydro- benzonitrile(E38) 1H-benzo[d]azepine (E5) 1-[4-(3-Cyclopentyl-2,3,4,5-3-Cyclopentyl-7- Isonicotinic acid 420 tetrahydro-1H-benzo[d]azepin-7-(piperidin-4-yloxy)- yloxy)-piperidin-1-yl]-1-pyridin-4-yl-2,3,4,5-tetrahydro- methanone (E39) 1H-benzo[d]azepine (E5)1-[4-(3-Cyclopentyl-2,3,4,5- 3-Cyclopentyl-7- Quinoline-6- 470tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- carboxylic acidyloxy)-piperidin-1-yl]-1-quinolin-6- 2,3,4,5-tetrahydro- yl-methanone(E40) 1H-benzo[d]azepine (E5) 1-[4-(3-Cyclopentyl-2,3,4,5-3-Cyclopentyl-7- 4-(1-Pyrrolidin-1- 516 tetrahydro-1H-benzo[d]azepin-7-(piperidin-4-yloxy)- yl-methanoyl)- yloxy)-piperidin-1-yl]-1-[4-(1-2,3,4,5-tetrahydro- benzoic acid (WO pyrrolidin-1-yl-methanoyl)-1H-benzo[d]azepine 03/04468A1) phenyl]methanone (E41) (E5)1-Biphenyl-4-yl-1-[4-(3- 3-Cyclopentyl-7- 4-Biphenyl 495cyclopentyl-2,3,4,5-tetrahydro-1H- (piperidin-4-yloxy)- carboxylic acidbenzo[d]azepin-7-yloxy)-piperidin- 2,3,4,5-tetrahydro- 1-yl]-methanone(E42) 1H-benzo[d]azepine (E5)

Example 431-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-cyclopentyl-methanone(E43)

3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) (150 mg, 0.5 mmol) was stirred in dichloromethane (5 ml) withdiethylaminomethyl polystyrene (3.2 mmol/g, 625 mg, 2 mmol).Cyclopentane carbonyl chloride (80 μl, 0.6 mmol) was added and themixture stirred at room temperature for 16 hours. The resin wasfiltered, washed with dichloromethane and the filtrate concentrated invacuo. The residue was purified by column chromatography eluting withdichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethane(1:9:90) to afford the title product (E43); MS (ES+) m/e 397 [M+H]⁺.

Examples 44-51

Examples 44-51 (E44-E51) were prepared using an analogous method to thatdescribed for Example 43 (E43) from the appropriate amine and carbonylchloride as indicated in the table:

Carbonyl LC/MS Example Amine chloride (M + H⁺⁾4-{1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- 4-Cyano benzoyl 444tetrahydro-1H-benzo[d]azepin-7- (piperidin-4- chlorideyloxymethyl)-piperidin-1-yl]- ylmethoxy)-2,3,4,5-methanoyl}-benzonitrile (E44) tetrahydro-1H- benzo[d]azepine (E7)4-{1-[(R)-2-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((R)- 4-Cyano benzoyl430 tetrahydro-1H-benzo[d]azepin-7- 1-pyrrolidin-2- chlorideyloxymethyl)-pyrrolidin-1-yl]- ylmethoxy)-2,3,4,5-methanoyl}-benzonitrile (E45) tetrahydro-1H- benzo[d]azepine (E8)4-{1-[(R)-3-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((R)- 4-Cyano-benzoyl416 tetrahydro-1H-benzo[d]azepin-7- pyrrolidin-3-yloxy)- chlorideyloxy)-pyrrolidin-1-yl]-methanoyl}- 2,3,4,5-tetrahydro- benzonitrile(E46) 1H-benzo[d]azepine (E9) 4-{1-[(S)-3-(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7-((S)- 4-Cyano-benzoyl 416 tetrahydro-1H-benzo[d]azepin-7-pyrrolidin-3-yloxy)- chloride yloxy)-pyrrolidin-1-yl]-methanoyl}-2,3,4,5-tetrahydro- benzonitrile (E47) 1H-benzo[d]azepine (E10)4-{1-[(S)-2-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((S)-1-4-Cyano-benzoyl 430 tetrahydro-1H-benzo[d]azepin-7- pyrrolidin-2-chloride yloxy)-pyrrolidin-1-yl]-methanoyl}- ylmethoxy)-2,3,4,5-benzonitrile (E48) tetrahydro-1H- benzo[d]azepine (E11)1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- 2,2-Dimethyl- 385tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- propionylyloxy)-piperidin-1-yl]-2,2-dimethyl- 2,3,4,5-tetrahydro- chloridepropan-1-one (E49) 1H-benzo[d]azepine (E6) 1-[4-(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7- Cyclopropane 369 tetrahydro-1H-benzo[d]azepin-7-(piperidin-4-yloxy)- carbonyl chloride yloxy)-piperidin-1-yl]-1-2,3,4,5-tetrahydro- cyclopropyl-methanone (E50) 1H-benzo[d]azepine (E6)1-Cyclobutyl-1-[4-(3-cyclobutyl- 3-Cyclobutyl-7- Cyclobutane 3832,3,4,5-tetrahydro-1H- (piperidin-4-yloxy)- carbonyl chloridebenzo[d]azepin-7-yloxy)- 2,3,4,5-tetrahydro- piperidine-1-yl]-methanone(E51) 1H-benzo[d]azepine (E6)

Example 524-{1-{4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-morpholin-4-yl-methanone(E52)

3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) (150 mg, 0.5 mmol) was stirred in dichloromethane (5 ml) withdiethylaminomethyl polystyrene (3.2 mmol/g, 625 mg, 2 mmol). Morpholinecarbamoyl chloride (70 μL, 0.6 mmol) was added and the mixture stirredat room temperature for 16 hours. The resin was filtered, washed withdichloromethane and the filtrate concentrated in vacuo. The residue waspurified by column chromatography eluting with dichloromethane then amixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford thetitle product (E52). MS (ES+) m/e 414 [M+H]⁺.

Examples 53-60

Examples 53-60 (E53-E60) were prepared using an analogous method to thatdescribed for Example 52 (E52) from the appropriate amine and carbonylchloride indicated in the table:

Carbonyl LC/MS Example Amine Chloride (M + H⁺⁾1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- Morpholine- 428tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-ylmethoxy)- 4-carbonylyloxymethyl)-piperidin-1-yl]-1- 2,3,4,5-tetrahydro-1H- chloridemorpholin-4-yl-methanone (E53) benzo[d]azepine (E7)1-[(R)-2-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((R)-1- Morpholine- 414tetrahydro-1H-benzo[d]azepin-7- pyrrolidin-2-ylmethoxy)- 4-carbonylyloxymethyl)-pyrrolidin-1-yl]-1- 2,3,4,5-tetrahydro-1H- chloridemorpholin-4-yl-methanone (E54) benzo[d]azepine (E8)1-[(R)-3-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((R)- Morpholine- 400tetrahydro-1H-benzo[d]azepin-7- pyrrolidin-3-yloxy)- 4-carbonylyloxy)-pyrrolidin-1-yl]-1-morpholin- 2,3,4,5-tetrahydro-1H- chloride4-yl-methanone (E55) benzo[d]azepine (E9)1-[(S)-3-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((S)- Morpholine- 400tetrahydro-1H-benzo[d]azepin-7- pyrrolidin-3-yloxy)- 4-carbonylyloxy)-pyrrolidin-1-yl]-1-morpholin- 2,3,4,5-tetrahydro-1H- chloride4-yl-methanone (E56) benzo[d]azepine (E10)4-(3-Cyclobutyl-2,3,4,5-tetrahydro- 3-Cyclobutyl-7- Diisopropyl- 4281H-benzo[d]azepin-7-yloxy)- (piperidin-4-yloxy)- carbonylpiperidine-1-carboxylic acid 2,3,4,5-tetrahydro-1H- chloridediisopropylamide (E57) benzo[d]azepine (E6) 1-[4-(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7- Pyrrolidine- 398 tetrahydro-1H-benzo[d]azepin-7-(piperidin-4-yloxy)- 1-carbonyl yloxy)-piperidin-1-yl]-pyrrolidin-1-2,3,4,5-tetrahydro-1H- chloride yl-methanone (E58) benzo[d]azepine (E6)1-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- Piperidine- 412tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- 1-carbonylyloxy)-piperidin-1-yl]-1-piperidin-1- 2,3,4,5-tetrahydro-1H- chlorideyl-methanone (E59) benzo[d]azepine (E6) 1-[(S)-2-(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7-((S)-1- Morpholine- 414 tetrahydro-1H-benzo[d]azepin-7-pyrrolidin-2-ylmethoxy)- 4-carbonyl yloxymethyl)-pyrrolidin-1-yl]-1-2,3,4,5-tetrahydro-1H- chloride morpholin-4-yl-methanone (E60)benzo[d]azepine (E11)

Example 614-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylicacid diethylamide (E61)

3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) (1.5 g, 5 mmol) dissolved in toluene (40 ml) was added slowly to a20% phosgene in toluene solution (12.5 ml, 25 mmol) at 0° C. The mixturewas stirred at room temperature for 3 hours and concentrated in vacuo toafford a crude residue (1.91 g). The crude product (300 mg, 0.75 mmol)was then added to a stirred slurry of diethylamine (207 μL, 2 mmol) anddiethylaminomethyl polystyrene (3.2 mmol/g, 1.41 g, 4.5 mmol) indichloromethane (10 ml). The reaction mixture was stirred at roomtemperature for 16 hours, filtered and concentrated in vacuo. The cruderesidue was purified by column chromatography eluting withdichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethane(1:9:90) to afford the title product (E61). MS (ES+) m/e 400 [M+H]⁺.

Examples 62-65

Examples 62-65 (E62-E65) were prepared using an analogous method to thatdescribed for Example 61 (E61) from3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) and the appropriate amine indicated in the table:

LC/MS Example Amine (M + H⁺⁾ 1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-2,3-Dihydro-1H- 446 1H-benzo[d]azepin-7-yloxy)-piperidin-1- isoindoleyl]-1-(1,3-dihydro-isoindol-2-yl)- methanone (E62)1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro- 3,4,5,6- 4911H-benzo[d]azepin-7-yloxy)-piperidin-1- Tetrahydro-2H-yl]-1-(2,3,5,6-tetrahydro- [1,2′]bipyrazinyl[1,2′]bipyrazinyl-4-yl)-methanone (E63)1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro- Isopropyl-(2- 4441H-benzo[d]azepin-7-yloxy)-piperidine- methoxy-ethyl- 1-carboxylic acidisopropyl-(2-methoxy- amine ethyl) amide (E64)1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro- Thiomorpholine 4621H-benzo[d]azepin-7-yloxy)-piperidin-1- 1,1-dioxideyl]-(1,1-dioxo-thiomorpholin-4-yl)- methanone (E65)

Example 664-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylicacid isopropylamide (E66)

A solution of3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) (150 mg, 0.5 mmol) and isopropyl isocyanate (60 μL, 0.6 mmol) indichloromethane (5 ml) was stirred at room temperature for 16 hours. Thesolution was concentrated in vacuo and the residue was purified bycolumn chromatography eluting with dichloromethane then a mixture of0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the titleproduct (E66). MS (ES+) m/e 386 [M+H]⁺.

Example 674-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylicacid (4-fluoro-phenyl)-amide (E67)

Example 67 was prepared from3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) and 4-fluorophenyl-isocyanate using the method described forExample 66 (E66); MS (ES+) m/e 438 [M+H]⁺.

Example 682-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N,N-dimethyl-acetamide(E68)

Sodium hydride (60% disp. in mineral oil, 60 mg, 1.5 mmol) was added toa stirred solution of3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, 0.9mmol) in dimethyl sulfoxide (10 ml). After 0.5 hours,2-chloro-N,N-dimethyl acetamide (0.3 ml, 2.4 mmol) was added and thereaction mixture was heated to 120° C. for 6 hours. The reaction wasallowed to cool, the crude mixture was applied to a SCX cartridge ionexchange (Varian bond-elute, 10 g) and washed with methanol and then amixture of 0.880 ammonia:methanol (1:9). The combined basic fractionswere reduced in vacuo to afford the title compound (E68). MS (ES+) m/e303 [M+H]⁺.

Examples 69-71

Examples 69-71 (E69-E71) were prepared using the method described forExample 68 (E68) from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and theappropriate chloride indicated in the table.

LC/MS Example Chloride (M + H⁺⁾ 2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-2-Chloro- 351 benzo[d]azepin-7-yloxy)-N-phenyl- N-phenyl- acetamide(E69) acetamide 2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 2-Chloro-1- 329benzo[d]azepin-7-yloxy)-1-pyrrolidin-1- pyrrolidin-1- yl-ethanone (E70)yl-ethanone 2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 2-Chloro-1- 345benzo[d]azepin-7-yloxy)-1-morpholin-4- morpholinyl- yl-ethanone (E71)4-yl-ethanone

Example 723-Cyclobutyl-7-(1-methanesulfonyl-piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E72)

3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) (150 mg, 0.5 mmol) was stirred in dichloromethane (5 ml) withdiethylaminomethyl polystyrene (3.2 mmol/g, 625 mg, 2 mmol). Methanesulfonyl chloride (43 μL, 0.55 mmol) was added and the mixture stirredat room temperature for 16 hours. The resin was filtered, washed withdichloromethane and the filtrate concentrated in vacuo. The residue waspurified by column chromatography eluting with a mixture of 0.880ammonia:ethanol:dichloromethane (1:9:90) to afford the title product(E72); MS (ES+) m/e 379 [M+H]⁺.

Examples 73-78

Examples 73-78 (E73-E78) were prepared using an analogous method to thatdescribed for Example 72 (E72) from the appropriate amine and sulfonylchloride indicated in the table:

Sulfonyl LC/MS Example Amine Chloride (M + H⁺⁾4-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- 4-Cyano- 466tetrahydro-1H-benzo[d]azepin-7- (piperidin-4-yloxy)- benzenesulfonylyloxy)-piperidine-1-sulfonyl]- 2,3,4,5-tetrahydro- chloride benzonitrile(E73) 1H-benzo[d]azepine (E6) 3-Cyclobutyl-7-[1-(3,5-dimethyl-3-Cyclobutyl-7- 3,5-Dimethyl- 460 isoxazole-4-sulfonyl)-piperidin-4-(piperidin-4-yloxy)- isoxazole-4- yloxy]-2,3,4,5-tetrahydro-1H-2,3,4,5-tetrahydro- sulfonyl benzo[d]azepine (E74) 1H-benzo[d]azepinechloride (E6) 4-[4-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7- 4-Cyano- 480tetrahydro-1H-benzo[d]azepin-7- (piperidin-4- benzenesulfonylyloxymethyl)-piperidine-1-sulfonyl]- ylmethoxy)-2,3,4,5- chloridebenzonitrile (E75) tetrahydro-1H- benzo[d]azepine (E7)4-[(R)-2-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((R)- 4-Cyano- 466tetrahydro-1H-benzo[d]azepin-7- 1-pyrrolidin-2- benzenesulfonylyloxymethyl)-pyrrolidine-1- ylmethoxy)-2,3,4,5- chloridesulfonyl]-benzonitrile (E76) tetrahydro-1H- benzo[d]azepine (E8)4-[(R)-3-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((R)- 4-Cyano- 452tetrahydro-1H-benzo[d]azepin-7- pyrrolidin-3-yloxy)- benzenesulfonylyloxy)-pyrrolidine-1-sulfonyl]- 2,3,4,5-tetrahydro- chloridebenzonitrile (E77) 1H-benzo[d]azepine (E9)4-[(S)-3-(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-((S)- 4-Cyano- 452tetrahydro-1H-benzo[d]azepin-7- pyrrolidin-3-yloxy)- benzenesulfonylyloxy)-pyrrolidine-1-sulfonyl]- 2,3,4,5-tetrahydro- chloridebenzonitrile (E78) 1H-benzo[d]azepine (E10)

Example 793-Cyclobutyl-7-(2,4-difluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E79)

Potassium carbonate (778 mg, 5.6 mmol) was added to a stirred solutionof 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (868 mg,4.0 mmol), 2,4-difluorobenzyl bromide (0.25 ml, 2.1 mmol) and potassiumiodide (25 mg) in butanone (9 ml). The reaction mixture was stirred atreflux for 18 hours, cooled, filtered and concentrated in vacuo. Thecrude residue was dissolved with ethyl acetate and washed with water andbrine. The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification of the resulting residue by columnchromatography eluting with a mixture of 0.880ammonia:ethanol:dichloromethane (0.25:2.25:97.5 then 1:9:10) affordedthe title compound (E79); MS (ES+) m/e 344 [M+H]⁺.

Examples 80-87

Examples 80-87 (E80-E87) were prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and theappropriate halide indicated in the table using the general methoddescribed for Example 80 (E80):

LC/MS Example Halide (M + H⁺⁾ 3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-Bromomethyl- 333 benzo[d]azepin-7-yloxymethyl)-benzonitrile (E80)benzonitrile 3-Cyclobutyl-7-(3-methoxy-benzyloxy)-2,3,4,5-1-Bromomethyl-3- 338 tetrahydro-1H-benzo[d]azepine (E81) methoxybenzene3-Cyclobutyl-7-(pyridin-2-ylmethoxy)-2,3,4,5- 2-Bromomethyl-pyridine 309tetrahydro-1H-benzo[d]azepine (E82)3-Cyclobutyl-7-(pyridin-3-ylmethoxy)-2,3,4,5- 3-Bromomethyl-pyridine 309tetrahydro-1H-benzo[d]azepine (E83)3-Cyclobutyl-7-(pyridin-4-ylmethoxy)-2,3,4,5- 4-Bromomethyl-pyridine 309tetrahydro-1H-benzo[d]azepine (E84)2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 2-Bromomethyl- 333benzo[d]azepin-7-yloxymethyl)-benzonitrile (E85) benzonitrile4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 4-Bromomethyl- 333benzo[d]azepin-7-yloxymethyl)-benzonitrile (E86) benzonitrile6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 6-Bromomethyl-1-methyl- 389benzo[d]azepin-7-yloxymethyl)-1-methyl-1H- 1H-quinolin-2-onequinolin-2-one (E87)

Example 884-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid methyl ester (E88)

4-(2,3,4,5-Tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acidmethyl ester (D4) (2.83 g, 9.1 mmol) and cyclopentanone (1.6 ml, 18.2mmol) were dissolved in dichloromethane (30 ml) and acetic acid (0.5ml). Sodium triacetoxy borohydride (3.85 g, 18.2 mmol) was added and thesolution was stirred at room temperature for 4 hours. The reactionmixture was washed with a saturated solution of sodium carbonate, theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude mixture was purified by columnchromatography eluting with a mixture of 0.880ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound(E88); MS (ES+) m/e 380 [M+H]⁺.

Example 894-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid (E89)

4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid methyl ester (E88) (3.1 g, 8.1 mmol)) was dissolved in a mixture ofmethanol (90 ml), 2N sodium hydroxide (12 ml) and water (30 ml). Theresulting mixture was stirred at 60° C. for 4 hours and then cooled toroom temperature. The mixture was concentrated in vacuo to remove theorganic solvents and then acidified to pH 6 (2N hydrochloric acid). Theresulting precipitates were filtered, washed with water and dried undervacuum to afford the title compound (E89); MS (ES+) m/e 366 [M+H]⁺.

Example 901-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-phenyl]-1-pyrrolidin-yl-methanone(E90)

4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid (E89) (0.201 mg, 0.55 mmol)), 1,3-diisopropylcarbodiimide (44 μl,0.6 mmol) and 1-hydroxybenzotriazole hydrate (82 mg, 0.6 mmol) weredissolved in a mixture of dichloromethane (2 ml) and dimethyl formamide(1 ml). After stirring at room temperature for 0.5 hours, pyrrolidine(41 μl, 0.5 mmol) was added and the resulting mixture was allowed tostir for 16 hours. The crude reaction was applied to a SCX ion exchangecartridge (Varian bond-elute, 5 g) and washed with methanol and then amixture of 0.880 ammonia:methanol (1:9). The combined basic fractionswere concentrated in vacuo, and the resulting residue was purified bycolumn chromatography eluting with a mixture of 0.880ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound(E90); MS (ES+) m/e 419 [M+H]⁺.

Examples 91-93

Examples 91-93 (E91-E93) were prepared using an analogous method to thatdescribed for Example 90 (E90) from4-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid (E89) and the appropriate amine indicated in the table:

LC/MS Example Amine (M + H⁺⁾ 1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-Morpholine 435 benzo[d]azepin-7-yloxymethyl)-phenyl]-1-morpholin-4-yl-methanone (E91)1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H- 1-Pyridin- 511benzo[d]azepin-7-yloxymethyl)-phenyl]-1-(4- 4-yl-pyridin-4-yl-piperazin-1-yl)-methanone (E92) piperazine1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H- 1-(4-Fluoro- 528benzo[d]azepin-7-yloxymethyl)-phenyl]- phenyl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]- piperazine methanone (E93)

Example 943-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid methyl ester (E94)

Example 94 (E94) was prepared in an analogous manner to Example 88 (E88)from 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (WO 02/40471) and 3-bromomethyl-benzoic acid methylester using the methods highlighted in Description 3 (D3), Description 4(D4) and Example 88 (E88); MS (ES+), m/e 380 [M+H]⁺.

Example 953-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid (E95)

Example 95 (E95) was prepared from3-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid methyl ester Example 94 (E94) using the procedure outlined forExample 89 (E89); MS (ES+), m/e 366 [M+H]⁺.

Example 961-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-phenyl]-1-pyrrolidin-yl-methanone(E96)

Example 96 (E96) was prepared from pyrrolidine and3-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid (E95) using the procedure outlined for Example 90 (E90); MS (ES+),m/e 419 [M+H]⁺.

Examples 97-99

Examples 97-99 (E97-E99) were prepared from3-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid (E95) and the appropriate amine indicated in the table using ananalogous method to that described for Example 96 (E96).

LC/MS Example Amine (M + H⁺⁾ 1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-Morpholine 435 benzo[d]azepin-7-yloxymethyl)-phenyl]-1-morpholin-4-yl-methanone (E97)1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H- 1-Pyridin- 511benzo[d]azepin-7-yloxymethyl)-phenyl]-1-(4- 4-yl-pyridin-4-yl-piperazin-1-yl)-methanone (E98) piperazine1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H- 1-(4-Fluoro- 528benzo[d]azepin-7-yloxymethyl)-phenyl]- phenyl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]- piperazine methanone (E99)

Example 1006-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotinonitrile(E100)

Sodium hydride (60% disp. in mineral oil, 60 mg, 1.5 mmol) was added toa stirred solution of3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, 0.9mmol) in dimethyl sulfoxide (10 ml). After 0.5 hours,6-chloronicotinylnitrile (250 mg, 1.8 mmol) was added and the reactionmixture was heated to 120° C. for 6 hours. The reaction was allowed tocool and the crude mixture was applied to a SCX ion exchange cartridge(Varian bond-elute, 10 g) and washed with methanol and then a mixture of0.880 ammonia:methanol (1:9). The combined basic fractions were reducedin vacuo to afford the title compound (E100); MS (ES+) m/e 320 [M+H]⁺.

Examples 101-120

Examples 101-120 (E101-E120) were prepared using an analogous method tothat described for Example 100 (E100) from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and theappropriate aromatic chloride indicated in the table:

LC/MS Example Chloride (M + H⁺⁾3-Cyclobutyl-7-(pyridin-2-yloxy)-2,3,4,5-tetrahydro- 2-Chloro-pyridine295 1H-benzo[d]azepine (E101) 1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-1-(6-Chloro-pyridin-3- 408benzo[d]azepin-7-yloxy)-pyridin-3-yl]-1-morpholin- yl)-1-morpholin-4-yl-4-yl-methanone (E102) methanone (D5)1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(6-Chloro-pyridin-3- 392benzo[d]azepin-7-yloxy)-pyridin-3-yl]-1-pyrrolidin-yl)-1-pyrrolidin-1-yl- 1-l-methanone (E103) methanone (D6)6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 6-Chloro-nicotinamide 338benzo[d]azepin-7-yloxy)-nicotinamide (E104) (D7)6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 6-Chloro-N,N-dimethyl- 366benzo[d]azepin-7-yloxy)-N,N-dimethyl- nicotinamide (D8) nicotinamide(E105) 6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 6-Chloro-N-ethyl-N- 380benzo[d]azepin-7-yloxy)-N-ethyl-N-methyl- methyl-nicotinamidenicotinamide (E106) (D9) 6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-6-Chloro-N-cyclopentyl- 406 benzo[d]azepin-7-yloxy)-N-cyclopentyl-nicotinamide (D11) nicotinamide (E107)1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(6-Chloro-pyridin-3- 406benzo[d]azepin-7-yloxy)-pyridin-3-yl]-1-piperidin-1-yl)-1-piperidin-1-yl- yl-methanone (E108) methanone (D12)1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(2-Chloro-pyridin-4- 406benzo[d]azepin-7-yloxy)-pyridin-4-yl]-1-piperidin-1-yl)-1-piperidin-1-yl- yl-methanone (E109) methanone (D13)1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(2-Chloro-pyridin-4- 392benzo[d]azepin-7-yloxy)-pyridin-4-yl]-1-pyrrolidin-yl)-1-pyrrolidin-1-yl- 1-yl-methanone (E110) methanone (D14)1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(2-Chloro-pyridin-4- 408benzo[d]azepin-7-yloxy)-pyridin-4-yl]-1-morpholin- yl)-1-morpholin-4-yl-4-yl-methanone (E111) methanone (D15)1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(6-Chloro-pyridin-2- 406benzo[d]azepin-7-yloxy)-pyridin-2-yl]-1-piperidin-1-yl)-1-piperidin-1-yl- yl-methanone (E112) methanone (D16)1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(6-Chloro-pyridin-2- 466benzo[d]azepin-7-yloxy)-pyridin-2-yl]-1-(1,1- yl)-1-(1,1-dioxothiomorpholin-4-yl)-methanone (E113) dioxothiomorpholin-4-yl)-methanone (D17) 1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-1-(6-Chloro-pyridin-2- 392benzo[d]azepin-7-yloxy)-pyridin-2-yl]-1-pyrrolidin-yl)-1-pyrrolidin-1-yl- 1-yl-methanone (E114) methanone (D18)1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(6-Chloro-pyridin-2- 408benzo[d]azepin-7-yloxy)-pyridin-2-yl]-1-morpholin- yl)-1-morpholin-4-yl-4-yl-methanone (E115) methanone (D19)1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(2-Chloro-pyridin-3- 408benzo[d]azepin-7-yloxy)-pyridin-3-yl]-1-morpholin- yl)-1-morpholin-4-yl-4-yl-methanone (E116) methanone (D20)1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(2-Chloro-pyridin-3- 406benzo[d]azepin-7-yloxy)-pyridin-3-yl]-1-piperidin-1-yl)-1-piperidin-1-yl- yl-methanone (E117) methanone (D21)3-Cyclobutyl-7-(pyrazin-2-yloxy)-2,3,4,5- 2-Chloro-pyrazine 296tetrahydro-1H-benzo[d]azepine (E118)3-Cyclobutyl-7-(pyrimidin-2-yloxy)-2,3,4,5- 2-Chloro-pyrimidine 296tetrahydro-1H-benzo[d]azepine (E119)7-(5-Bromo-pyrimidin-2-yloxy)-3-Cyclobutyl- 5-Bromo-2-chloro- 3752,3,4,5-tetrahydro-1H-benzo[d]azepine (E120) pyrimidine

Example 1216-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl-nicotinamide(E121)

Sodium hydride (60% disp. in mineral oil, 60 mg, 1.5 mmol) was added toa stirred solution of3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, 0.9mmol) in dimethyl sulfoxide (10 ml). After 0.5 hours,6-chloro-N-methyl-nicotinamide (D10) (400 mg, 2.5 mmol) was added andthe reaction mixture was heated to 120° C. for 6 hours. The reaction wasallowed to cool and the crude mixture was applied to a SCX ion exchangecartridge (Varian bond-elute, 10 g) and washed with methanol and then amixture of 0.880 ammonia:methanol (1:9). The combined basic fractionswere reduced in vacuo to afford the title compound (E121). ¹H NMR(DMSO-d₆) δ 8.56 (1H, dd, J=2.4, 0.4 Hz), 8.48 (1H, br m), 8.20 (1H, dd,J=8.4, 2.4 Hz), 7.16 (1H, d, J=8.0 Hz), 7.03 (1H, dd, J=8.4, 0.4 Hz),6.91 (1H, d, J=2.4 Hz), 6.86 (1H, dd, J=8.0, 2.4 Hz), 2.87-2.77 (8H, m),2.36 (4H, m), 2.00 (2H, m), 1.78 (2H, m), 1.58 (2H, m); MS (ES+) m/e 352[M+H]⁺.

Example 121 Alternative Procedure 16-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl-nicotinamide(E121)

Sodium hydride (0.331 g, 8.28 mmol, 60% disp. in mineral oil) was addedto a stirred solution of3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.5 g, 6.9mmol) in dimethyl sulfoxide (15 ml). After 0.5 hours,6-chloro-N-methyl-nicotinamide (D10) (2.34 g, 13.8 mmol) was added andthe reaction mixture was heated to 100° C. for 18 hours. The reactionwas allowed to cool to room temperature and then partitioned betweenethyl acetate and water. The ethyl acetate layer was separated and thewater layer washed with further volumes of ethyl acetate. The combinedorganic layers were then washed with water, brine, dried (Na₂SO₄) andthen filtered. The mixture was concentrated in vacuo and the resultingresidue was purified by column chromatography eluting with a mixture of0.880 ammonia:ethanol:dichloromethane (0.5:4.5:95 then 1:9:90) to affordthe title compound (E121) which then was recrystallised from toluene. ¹HNMR (DMSO-d₆) δ 8.56 (1H, dd, J=2.4, 0.4 Hz), 8.48 (1H, br m), 8.20 (1H,dd, J=8.4, 2.4 Hz), 7.16 (1H, d, J=8.0 Hz), 7.03 (1H, dd, J=8.4, 0.4Hz), 6.91 (1H, d, J=2.4 Hz), 6.86 (1H, dd, J=8.0, 2.4 Hz), 2.87-2.77(8H, m), 2.36 (4H, m), 2.00 (2H, m), 1.78 (2H, m), 1.58 (2H, m); MS(ES+) m/e 352 [M+H]⁺.

Example 121 Alternative Procedure 26-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl-nicotinamide(E121)

A mixture ofN-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide(D40) (1.04 g, 3.5 mmol) in dichloromethane (12 ml) containing aceticacid (240 μL) at 0° C. was treated dropwise with cyclobutanone (400 μL,5.3 mmol) and then stirred at room temperature for 1 hour. The mixturewas then cooled to 0° C. and treated portionwise with sodiumtriacetoxyborohydride (1.11 g, 5.3 mmol) and stirred at room temperaturefor 16 hours. The solution was carefully basified with 2N sodiumhydroxide, stirred for 30 minutes and then extracted withdichloromethane. The combined extracts were washed with brine, driedover anhydrous sodium sulphate and concentrated in vacuo. The crudematerial was purified by column chromatography eluting withdichloromethane then a mixture of 0.880 ammonia:methanol:dichloromethane(1:9:90) to afford the title compound (E121); MS (ES+) m/e 352 [M+H]⁺.

Example 1225-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylicacid methyl ester (E122)

Sodium hydride (60% disp. in mineral oil, 332 mg, 8.3 mmol) was added toa stirred solution of3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.64 g, 7.5mmol) in dimethyl formamide (4 ml). After 0.5 hours, a solution of5-chloro-pyrazine-2-carboxylic acid methyl ester (1.95 g, 11.3 mmol) indimethyl formamide (8 ml) was added and the reaction mixture was stirredat room temperature for 1 hour. The reaction mixture was diluted withdichloromethane and the organic layer was washed with water, brine anddried over magnesium sulfate. The organic layer was filtered,concentrated in vacuo and the resulting residue was purified by columnchromatography eluting with a mixture of 0.880ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound(E122). MS (ES+) m/e 354 [M+H]⁺.

Example 123a5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylicacid (E123a)

5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylicacid methyl ester (E122) (880 mg, 2.5 mmol) was dissolved in a mixtureof ethanol (15 ml) and 2N sodium hydroxide (4 ml). The resulting mixturewas stirred at room temperature for 0.5 hours and then concentrated invacuo to remove the organic solvents. The reaction mixture was thenacidified to pH 5 (2N hydrochloric acid) and the resulting precipitateswere filtered, washed with water and dried under vacuum to afford thetitle compound (E123a); MS (ES+) m/e 340 [M+H]⁺.

Example 1231-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazin-2-yl]-1-morpholin-4-yl-methanone(E123)

Step 1:5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carbonylchloride

Thionyl chloride (5 ml) was added slowly to5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylicacid (E123a) (485 mg). The resulting reaction mixture was stirred atroom temperature for 1 hour and then heated at reflux for a further 1hour. The reaction mixture was cooled, diluted with toluene andconcentrated in vacuo to afford the title compound which was usedwithout further characterisation.

Step 2:1-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazin-2-yl]-1-morpholin-4-yl-methanone

Morpholine (0.17 ml, 2.0 mmol) was added to a stirred solution of theproduct of step 1 (394 mg, 1 mmol) and diethylaminomethyl polystyrene(1.88 g, 3.2 mmol/g, 6 mmol) in dichloromethane (10 ml). The resultingmixture was allowed to stir at room temperature for 24 hours and thefiltered. The filtrate was concentrated in vacuo and the resulting cruderesidue was purified column chromatography eluting with a mixture of0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the titlecompound (E123). MS (ES+) m/e 409 [M+H]⁺.

Examples 124 and 126-127

Examples 124 and 126-127 (E124 and E126-E127) were prepared from theproduct of Example 123, step 1 and the appropriate amine indicated inthe table using an analogous method to that described for Example 123,step 2:

LC/MS Example Amine (M + H⁺⁾ 5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-N-Ethylmethyl 381 benzo[d]azepin-7-yloxy)-pyrazine-2- amine carboxylicacid ethylmethyl amide (E124) 1-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-Piperidine 407 benzo[d]azepin-7-yloxy)-pyrazin-2-yl]-1-piperidin-4-yl-methanone (E126)1-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- Pyrrolidine 393benzo[d]azepin-7-yloxy)-pyrazin-2-yl]-1- pyrrolidin-4-yl-methanone(E127)

Example 1255-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylicacid methyl amide (E125)

The product of Example 123, step 1 (1.59 mmol) in dry dichloromethane(10 ml) was treated with methylamine (5 ml, 10 mmol, 2M solution in THF)and stirred at room temperature for 18 hours. The mixture was reduced invacuo and the resulting crude material was applied to a SCX ion exchangecartridge (Varian bond-elute, 10 g) and washed with methanol and then amixture of 0.880 ammonia:methanol (1:9). The basic fractions were thenreduced and the crude product purified by column chromatography elutingwith a mixture of 0.880 ammonia:ethanol:dichloromethane (0.2:1.8:98 andthen 0.4:3.6:96) to afford the title compound (E125). ¹H NMR (CDCl₃) δ8.91 (1H, d, 1.3 Hz), 8.26 (1H, d, 1.3 Hz), 7.61 (1H, br quartet, 4.8Hz), 7.15 (1H, m), 6.92 (2H, m), 3.03 (3H, d, 5.1 Hz), 2.93 (4H, m),2.79 (1H, m), 2.47 (4H, m), 2.08 (2H, m), 1.91 (2H, m), 1.70-1.62 (2H,m).

Example 128 3-Cyclobutyl-7-phenoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E128)

Sodium hydride (60% disp. in mineral oil, 96 mg, 2.4 mmol) was added toa stirred solution of3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (435 mg, 2.0mmol) and copper (I) bromide (402 mg, 2.8 mmol) in pyridine (10 ml) at0° C. After stirring for 0.5 hour at room temperature, iodobenzene (0.45ml, 4.0 mmol) was added and the reaction mixture was heated to refluxfor 24 hours. The reaction was allowed to cool, filtered and thefiltrate then concentrated in vacuo. The crude residue was dissolvedwith ethyl acetate and washed with water and brine. The organic layerwas dried over magnesium sulfate, filtered and concentrated in vacuo andthe resulting residue purified by column chromatography eluting with amixture of 0.880 ammonia:ethanol:dichloromethane (0.25:2.25:97.5 to1:9:90) to afford the title compound (E128); MS (ES+) m/e 294 [M+H]⁺.

Examples 129-138

Examples 129-138 (E129-E138) were prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and theappropriate aromatic halide indicated in the table using an analogousmethod to that described for Example 128 (E128):

LC/MS Example Aromatic halide (M + H⁺⁾1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(4-Iodo-phenyl)-1- 407benzo[d]azepin-7-yloxy)-phenyl]-1-morpholin-4-yl- morpholin-4-yl-methanone (E129) methanone (D22) 4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-4-Iodo-N- 391 benzo[d]azepin-7-yloxy)-N-cyclopropylmethyl-cyclopropylmethyl- benzamide (E130) benzamide (D23)1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(4-Iodo-phenyl)-1- 391benzo[d]azepin-7-yloxy)-phenyl]-1-pyrrolidin-1-yl- pyrrolidin-1-yl-methanone (E131) methanone (D24)N-Cyclobutyl-4-(3-Cyclobutyl-2,3,4,5-tetrahydro- 4-Iodo-N-cyclobutyl-391 1H-benzo[d]azepin-7-yloxy)-benzamide (E132) benzamide (D25)4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 4-Iodo-N,N-diethyl- 393benzo[d]azepin-7-yloxy)-N,N-diethyl-benzamide benzamide (D26) (E133)N-(2-Cyano-ethyl)-4-(3-cyclobutyl-2,3,4,5- 4-Iodo-N-(2-cyano- 404tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl- ethyl)-N-methyl-benzamide (E134) benzamide (D27)1-[3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H- 1-(3-Iodo-phenyl)-1- 407benzo[d]azepin-7-yloxy)-phenyl]-1-morpholin-4-yl- morpholin-4-yl-methanone (E135) methanone (D28) 3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-Iodo-N- 391 benzo[d]azepin-7-yloxy)-N-cyclopropylmethyl-cyclopropylmethyl- benzamide (E136) benzamide (D29)3-Cyclobutyl-7-[4-(morpholine-4-sulfonyl)- 4-(4-Iodo- 443phenoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepine benzenesulfonyl)- (E137)morpholine (D30) 4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-4-Iodo-N,N-diethyl- 429 benzo[d]azepin-7-yloxy)-N,N-diethyl-benzenesulfonamide benzenesulfonamide (E138) (D31)

Example 1397-Benzyloxy-3-cyclohexyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E139)

Example 139 (E139) was prepared from Description 2 (D2) andcyclohexanone using the method described for Example 1; MS (ES+) m/e 336[M+H]⁺.

Example 1403-Cyclobutyl-7-{[2-(1-piperidinyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E140)

Sodium hydride (60% disp. in mineral oil, 44 mg, 1.1 mmol) was added toa stirred solution of3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg,0.92 mmol) and copper (I) bromide (184 mg, 1.3 mmol) in pyridine (10 ml)at 0° C. After stirring for 0.5 hour at room temperature,5-bromo-2-(1-piperidinyl)pyrimidine (D32) (0.669 g, 2.8 mmol) was addedand the reaction mixture heated at reflux for 2 hours. The reaction wasallowed to cool, filtered and the filtrate was concentrated in vacuo.The crude residue was dissolved with ethyl acetate and washed with waterand brine. The organic layer was dried (magnesium sulfate), filtered andconcentrated in vacuo. Purification of the resulting residue by columnchromatography eluting with a mixture of 0.880ammonia:ethanol:dichloromethane (0.25:2.25:97.5 to 1:9:90) afforded thetitle compound (E140). MS (ES+) m/e 379 [M+H]⁺.

Examples 141-143

Examples 141-143 (E141-E143) were prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and theappropriate bromides indicated in the table using an analogous method tothat described for Example 140 (E140):

LC/MS Example Bromide (M + H⁺) 3-Cyclobutyl-7-{[2-(1-pyrrolidinyl)-5-5-Bromo-2-(1- 365 pyrimidinyl]oxy}-2,3,4,5-tetrahydro- pyrrolidinyl)1H-3-benzazepine (E141) pyrimidine (D33)3-Cyclobutyl-7-{[2-(1,1-dioxido-4- 4-(5-Bromo-2- 429thiomorpholinyl)-5-pyrimidinyl]oxy}- pyrimidinyl)2,3,4,5-tetrahydro-1H-3-benzazepine thiomorpholine (E142) 1,1-dioxide(D34) 5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- 5-Bromo-N- 325benzazepin-7-yl)oxy]-N-methyl-2- methyl-2- pyrimidinamine (E143)pyrimidinamine (D35)

Example 1443-Cyclobutyl-7-{[2-(methyloxy)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E144)

Example 144 (E144) was prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and5-bromo-2-(methyloxy)pyrimidine (PCT Int. Appl. PCT (2002), WO 02/62423)using the method described for Example 140 (E140); MS (ES+) m/e 326[M+H]⁺.

Examples 145-147

Examples 145-147 (E145-E147) were prepared from3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) and the appropriate acid indicated in the table using an analogousmethod to that described for Example 13 (E13):

LC/MS Example Acid (M + H⁺)1-[4-({4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- 4-(2-Oxo-1- 488benzazepin-7-yl)oxy]-1-piperidinyl}carbonyl)phenyl]-2- pyrrolidinyl)pyrrolidinone (E145) benzoic acid3-Cyclobutyl-7-[(1-{[3-(methylsulfonyl)phenyl]carbonyl}-3-(Methylsulfonyl) 4834-piperidinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine benzoic acid(E146) 3-Cyclobutyl-7-({1-[(1,1-dioxido-3,4-dihydro-2H-1-3,4-Dihydro-2H-1- 509 benzothiopyran-6-yl)carbonyl]-4-piperidinyl}oxy)-benzothiopyran- 2,3,4,5-tetrahydro-1H-3-benzazepine (E147) 6-carboxylicacid 1,1-dioxide

Examples 148-150

Examples 148-150 (E148-E150) were prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and theappropriate alcohol indicated in the table the method used for thepreparation of Example 5a (E5a) followed by the method described for thepreparation of Example 5 (E5).

LC/MS Example Alcohol (M + H⁺) 3-Cyclobutyl-7-{[(3S)-3-1,1-Dimethylethyl (3S)-3- 301 pyrrolidinylmethyl]oxy}-2,3,4,5-(hydroxymethyl)-1- tetrahydro-1H-3-benzazepine pyrrolidinecarboxylate(E148) 3-Cyclobutyl-7-{[(3S)-3- 1,1-Dimethylethyl (3S)-3- 315piperidinylmethyl]oxy}-2,3,4,5- (hydroxymethyl)-1-tetrahydro-1H-3-benzazepine piperidinecarboxylate (E149)3-Cyclobutyl-7-[(3S)-3- 1,1-Dimethylethyl (3S)-3- 301piperidinyloxy]-2,3,4,5- hydroxy-1- tetrahydro-1H-3-benzazepinepiperidinecarboxylate (E150)

Examples 151-153

Examples 151-153 (E151-E153) were prepared from the appropriate amineindicated in the table and morpholine carbamoyl chloride using themethod described for Example 52:

LC/MS Example Amine (M + H⁺⁾ 3-Cyclobutyl-7-({[(3S)-1-(4-3-Cyclobutyl-7-{[(3S)-3-piperidinyl 428morpholinylcarbonyl)-3-piperidinyl] methyl]oxy}-2,3,4,5-tetrahydro-methyl}oxy)-2,3,4,5-tetrahydro-1H-3- 1H-3-benzazepine (E149) benzazepine(E151) 3-Cyclobutyl-7-({[(3S)-1-(4- 3-Cyclobutyl-7-{[(3S)-3- 414morpholinylcarbonyl)-3-pyrrolidinyl] pyrrolidinylmethyl]oxy}-2,3,4,5-methyl}oxy)-2,3,4,5-tetrahydro-1H-3- tetrahydro-1H-3-benzazepinebenzazepine (E152) (E148) 3-Cyclobutyl-7-{[(3S)-1-(4-morpholinyl3-Cyclobutyl-7-[(3S)-3- 414 carbonyl)-3-piperidinyl]oxy}-2,3,4,5-piperidinyloxy]-2,3,4,5-tetrahydro- tetrahydro-1H-3-benzazepine (E153)1H-3-benzazepine (E150)

Examples 154-156

Examples 154-156 (E154-E156) were prepared from the appropriate amineindicated in the table and 4-cyanobenzoyl chloride using an analogousmethod to that described for Example 43 (E43):

LC/MS Example Amine (M + H⁺⁾ 4-[((3S)-3-{[(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7-{[(3S)-3- 444 tetrahydro-1H-3-benzazepin-7-piperidinylmethyl]oxy}-2,3,4,5- yl)oxy]methyl}-1-piperidinyl)carbonyl]tetrahydro-1H-3-benzazepine benzonitrile (E154) (E149)4-[((3S)-3-{[(3-Cyclobutyl-2,3,4,5- 3-Cyclobutyl-7-{[(3S)-3- 430tetrahydro-1H-3-benzazepin-7- pyrrolidinylmethyl]oxy}-2,3,4,5-yl)oxy]methyl}-1-pyrrolidinyl)carbonyl] tetrahydro-1H-3-benzazepinebenzonitrile (E155) (E148) 4-({(3S)-3-[(3-Cyclobutyl-2,3,4,5-3-Cyclobutyl-7-[(3S)-3- 430 tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyloxy]-2,3,4,5-tetrahydro- piperidinyl}carbonyl)benzonitrile(E156) 1H-3-benzazepine (E150)

Examples 157-159

Examples 157-159 (E157-E159) were from prepared from the appropriateamine indicated in the table and tetrahydro-pyran-4-carboxylic acidusing an analogous method to that described for Example 13 (E13):

LC/MS Example Amine (M + H⁺⁾ 3-Cyclobutyl-7-({[(3S)-1-(tetrahydro-2H-3-Cyclobutyl-7-{[(3S)-3- 413 pyran-4-ylcarbonyl)-3-pyrrolidinyl]methyl}pyrrolidinylmethyl]oxy}-2,3,4,5-oxy)-2,3,4,5-tetrahydro-1H-3-benzazepine tetrahydro-1H-3-benzazepine(E157) (E148) 3-Cyclobutyl-7-({[(3S)-1-(tetrahydro-2H-3-Cyclobutyl-7-{[(3S)-3- 427 pyran-4-ylcarbonyl)-3-piperidinyl]methyl}piperidinylmethyl]oxy}-2,3,4,5- oxy)-2,3,4,5-tetrahydro-1H-3-benzazepinetetrahydro-1H-3-benzazepine (E158) (E149)3-Cyclobutyl-7-{[(3S)-1-(tetrahydro-2H- 3-Cyclobutyl-7-[(3S)-3- 413pyran-4-ylcarbonyl)-3-piperidinyl]oxy}-piperidinyloxy]-2,3,4,5-tetrahydro- 2,3,4,5-tetrahydro-1H-3-benzazepine1H-3-benzazepine (E150) (E159)

Example 1606-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}-3-pyridinecarbonitrile(E160)

3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) (60 mg, 0.2 mmol), 6-chloronicotinonitrile (31 mg, 0.22 mmol) andtriethylamine (0.03 ml, 0.22 mmol) were dissolved in acetonitrile (2 ml)and heated to 180° C. in a microwave reactor for 10 minutes. Thereaction mixture was diluted with ethyl acetate and washed with water,brine and dried (magnesium sulfate). The organic layer was filtered,concentrated in vacuo and the resulting residue purified by columnchromatography eluting with a mixture of 0.880ammonia:ethanol:dichloromethane (0.25:2.25:97.5 to 1:9:90) to afford thetitle compound (E160); MS (ES+) m/e 403 [M+H]⁺.

Examples 161-166

Examples 161-166 (E161-E166) were prepared from3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) and the appropriate chloride indicated in the table using ananalogous method to that described for Example 160 (E160):

LC/MS Example Chloride (M + H⁺⁾6-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- 6-Chloro-N- 475benzazepin-7-yl)oxy]-1-piperidinyl}-N- (cyclopropylmethyl)-3-(cyclopropylmethyl)-3-pyridinecarboxamide pyridinecarboxamide (D36)(E161) 7-({1-[5-(1-Azetidinylcarbonyl)-2-pyridinyl]-4-5-(1-Azetidinylcarbonyl)-2- 461 piperidinyl}oxy)-3-cyclobutyl-2,3,4,5-chloropyridine (D37) tetrahydro-1H-3-benzazepine (E162)3-Cyclobutyl-7-({1-[5-(4-morpholinylcarbonyl)-1-(6-Chloro-pyridin-3-yl)-1- 4912-pyridinyl]-4-piperidinyl}oxy)-2,3,4,5- morpholin-4-yl-methanonetetrahydro-1H-3-benzazepine (E163) (D5)6-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- 6-Chloro-N-methyl- 435benzazepin-7-yl)oxy]-1-piperidinyl}-N-methyl- nicotinamide (D10)3-pyridinecarboxamide (E164)2-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- 2-Chloro-4-pyridine 403benzazepin-7-yl)oxy]-1-piperidinyl}-4- carbonitrile pyridinecarbonitrile(E165) 3-Cyclobutyl-7-{[1-(2-pyrazinyl)-4- 2-Chloropyrazine 379piperidinyl]oxy}-2,3,4,5-tetrahydro-1H-3- benzazepine (E166)

Example 167a Ethyl4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoate(E167a)

Ethyl 4-bromobutyrate (2 ml, 13.8 mmol) was added to a stirred solutionof 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (2.00 g,9.2 mmol) and potassium carbonate (3.8 g, 27.6 mmol) in 2-butanone (50ml). After stirring at reflux for 24 hours, the reaction mixture wascooled to room temperature, filtered and concentrated in vacuo. Theresulting crude material was purified by column chromatography elutingwith a mixture of methanol:dichloromethane (5:95) to afford the titlecompound (E167a). MS (ES+) m/e 332 [M+H]⁺

Example 167b4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoicacid (E167b)

Ethyl4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoate(E167a) (1.5 g, 4.5 mmol) was diluted in ethanol (30 ml) and treatedwith 2N sodium hydroxide (7.9 ml). After stirring at reflux for 24hours, the reaction mixture was cooled to room temperature, filtered andconcentrated in vacuo. The crude mixture was applied to a SCX ionexchange cartridge (Varian bond-elute) and washed with water, methanoland then a mixture of 0.880 ammonia:methanol (1:9). The combined basicfractions were reduced in vacuo to afford the title compound (E167b) asthe ammonium salt. MS (ES+) m/e 303 [M+H]⁺

Example 1673-Cyclobutyl-7-{[4-oxo-4-(1-piperidinyl)butyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E167)

Step 1:3-Cyclobutyl-7-{[4-(1H-imidazol-1-yl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine

4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoicacid (E167b) (0.90 g, 2.8 mmol) was dissolved in dimethylformamide (10ml) and treated with 1,1′-carbonyl diimidazole (0.59 g, 3.6 mmol). Afterstirring at room temperature for 2.5 hours, the reaction mixtureconcentrated in vacuo. The crude residue was dissolved indichloromethane, washed with brine and dried (sodium sulfate). Theorganic layer was filtered and concentrated in vacuo and the cruderesidue used directly in the next step without further purification.

Step 2:3-Cyclobutyl-7-{[4-oxo-4-(1-piperidinyl)butyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E167)

Piperidine (0.1 ml, 1.1 mmol) was added to a stirred solution of3-cyclobutyl-7-{[4-(1H-imidazol-1-yl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E167, Step 1) (150 mg, 0.42 mmol) in dichloromethane (5 ml). Afterstirring at room temperature for 5 days the reaction mixture wasconcentrated in vacuo and the resulting residue was purified by columnchromatography eluting with a mixture of 0.880ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound(E167); MS (ES+) m/e 371 [M+H]⁺.

Examples 168-170

Examples 168-170 (E168-E170) were prepared from Example 167 Step 1,using an analogous method to that described for Example 167 Step 2substituting piperidine for the appropriate amine indicated in thetable:

LC/MS Example Amine (M + H⁺⁾3-Cyclobutyl-7-{[4-oxo-4-(1-pyrrolidinyl)butyl]oxy}- Pyrrolidine 3572,3,4,5-tetrahydro-1H-3-benzazepine (E168)4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7- Cyclopentylamine371 yl)oxy]-N-cyclopentylbutanamide (E169)4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7- Methylamine 317yl)oxy]-N-methylbutanamide (E170)

Examples 171-176

Examples 171-176 (E171-E176) were prepared from Example 123, Step 1 andthe appropriate amine indicated in the table using an analogous methodto that described for Example 123 Step 2 (E123):

LC/MS Example Amine (M + H⁺⁾ 5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-Isopropylamine 381 benzazepin-7-yl)oxy]-N-(1-methylethyl)-2-pyrazinecarboxamide (E171) 5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-Tetrahydro-2H-pyran-4- 423benzazepin-7-yl)oxy]-N-(tetrahydro-2H-pyran-4- amineyl)-2-pyrazinecarboxamide (E172)7-{[5-(1-Azetidinylcarbonyl)-2-pyrazinyl]oxy}-3- Azetidine 379cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine (E173)5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Diethylamine 395benzazepin-7-yl)oxy]-N,N-diethyl-2- pyrazinecarboxamide (E174)5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- 2-(Methyloxy)ethylamine 397benzazepin-7-yl)oxy]-N-[2-(methyloxy)ethyl]-2- pyrazinecarboxamide(E175) 5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Ethylamine 367benzazepin-7-yl)oxy]-N-ethyl-2- pyrazinecarboxamide (E176)

Example 177a5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarbonitrile(E177a)

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) (1.81 g, 8.33mmol) was dissolved in pyridine (40 ml) and sodium hydride (60% inmineral oil, 0.40 g, 10.0 mmol) was added with stirring under argon at0° C. The mixture was left to stir for 5 minutes. Copper (I) bromide(1.68 g, 11.7 mmol) was added and the mixture allowed to warm to roomtemperature over 30 minutes. 5-Bromo-2-pyrimidinecarbonitrile (D38)(2.30 g, 12.5 mmol) in pyridine (8 ml) was added and the mixture heatedat 100° C. for 1 hour. The mixture was allowed to cool to roomtemperature and the solvent removed in vacuo. The crude product waspurified by column chromatography, eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the titlecompound (E177a); MS (ES+) m/e 321 [M+H]⁺.

Example 177b5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarboxylicacid (E177b)

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarbonitrile(E177a) (1.22 g, 3.81 mmol) was dissolved in ethanol (20 ml), treatedwith 10% sodium hydroxide solution (20 ml) and heated under reflux for90 minutes. The mixture was cooled to room temperature and applied to aSCX ion exchange column (Varian bond-elute, 10 g) eluting with water,methanol and then a mixture of 0.880 ammonia:methanol (1:9). The basicfractions were combined and concentrated in vacuo to afford the titlecompound (E177b); MS (ES+) m/e 340 [M+H]⁺.

Example 1773-Cyclobutyl-7-{[2-(4-morpholinylcarbonyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E177)

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarboxylicacid (E177b) (130 mg, 0.37 mmol) was dissolved in dimethylformamide (4ml), treated with 1,1′-carbonyldiimidazole (180 mg, 1.11 mmol) and leftto stir under argon at room temperature for 5 hours. The mixture wastreated with morpholine (0.19 ml, 2.22 mmol) and allowed to stir at roomtemperature for 18 hours. The reaction mixture was concentrated in vacuoand the resulting residue purified by column chromatography eluting witha mixture of 0.880 ammonia:methanol:dichloromethane (0.5:1.5:95) toafford the title compound (E177). MS (ES+) m/e 409 [M+H]⁺.

Examples 178-186

Examples 178-186 (E178-E186) were prepared from Example 177b (E177b) andthe appropriate amine indicated in the table using an analogous methodto that described for Example 177 (E177):

LC/MS Example Amine (M + H⁺⁾ 5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-Cyclopropylmethylamine 393 benzazepin-7-yl)oxy]-N-(cyclopropylmethyl)-2-pyrimidinecarboxamide (E178) 5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-Ethylamine 367 benzazepin-7-yl)oxy]-N-ethyl-2- pyrimidinecarboxamide(E179) 7-{[2-(1-Azetidinylcarbonyl)-5-pyrimidinyl]oxy}-3- Azetidine 379cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine (E180)5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Ethyl(methyl)amine 381benzazepin-7-yl)oxy]-N-ethyl-N-methyl-2- pyrimidinecarboxamide (E181)N-Cyclobutyl-5-[(3-cyclobutyl-2,3,4,5-tetrahydro- Cyclobutylamine 3931H-3-benzazepin-7-yl)oxy]-2- pyrimidinecarboxamide (E182)5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Tetrahydro-2H-pyran-4- 423benzazepin-7-yl)oxy]-N-(tetrahydro-2H-pyran-4- amineyl)-2-pyrimidinecarboxamide (E183)3-Cyclobutyl-7-{[2-(1-pyrrolidinylcarbonyl)-5- Pyrrolidine 393pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3- benzazepine (E184)3-Cyclobutyl-7-{[2-(1-piperidinylcarbonyl)-5- Piperidine 407pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3- benzazepine (E185)5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Methylamine 353benzazepin-7-yl)oxy]-N-methyl-2- pyrimidinecarboxamide(E186)

Example 187a5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyridinecarboxylicacid (E187a)

The title compound (E187a) was prepared from5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyridinecarbonitrile(E206) using an analogous method to that described for Example 177b(E177b); MS (ES+) m/e 339 [M+H]⁺.

Examples 187-195

Examples 187-195 (E187-E195) were prepared from5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyridinecarboxylicacid (E187a) and the appropriate amine indicated in the table using ananalogous method to that described for Example 177 (E177):

LC/MS Example Amine (M + H⁺⁾ 5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-Methylamine 352 benzazepin-7-yl)oxy]-N-methyl-2- pyridinecarboxamide(E187) 5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Ethylamine 366benzazepin-7-yl)oxy]-N-ethyl-2- pyridinecarboxamide (E188)5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Ethyl(methyl)amine 380benzazepin-7-yl)oxy]-N-ethyl-N-methyl-2- pyridinecarboxamide (E189)5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Diethylamine 394benzazepin-7-yl)oxy]-N,N-diethyl-2- pyridinecarboxamide (E190)5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Ethyl[2- 424benzazepin-7-yl)oxy]-N-ethyl-N-[2- (methyloxy)ethyl]amine(methyloxy)ethyl]-2-pyridinecarboxamide (E191)3-Cyclobutyl-7-{[6-(1-pyrrolidinylcarbonyl)-3- Pyrrolidine 392pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3- benzazepine (E192)3-Cyclobutyl-7-{[6-(4-morpholinylcarbonyl)-3- Morpholine 408pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3- benzazepine (E193)3-Cyclobutyl-7-{[6-(tetrahydro-1,4-oxazepin- Hexahydro-1,4- 4224(5H)-ylcarbonyl)-3-pyridinyl]oxy}-2,3,4,5- oxazepinetetrahydro-1H-3-benzazepine (E194)5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Cyclopentylamine 406benzazepin-7-yl)oxy]-N-cyclopentyl-2- pyridinecarboxamide (E195)

Example 196a6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxylicacid methyl ester

The title compound was prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and methyl6-chloro-3-pyridine carboxylate in an analogous manner to that describedfor E122; MS (ES+) m/e 353 [M+H]⁺.

Example 196b6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxylicacid (E196b)

The title compounds was prepared from Example 196a (E126a) using theanalogous methods to that described for Example 123a (E123a); MS (ES+)m/e 339 [M+H]⁺.

Example 1966-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-cyclopropyl-3-pyridinecarboxamide(E196)

Carbonyl diimidazole (142 mg, 0.88 mmol) was added to a stirred solutionof6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxylicacid (E196b) (150 mg, 0.44 mmol) in dichloromethane (5 ml). Afterstirring at room temperature for 3 hours, cyclopropylamine (0.15 ml, 2.2mmol) was added and the mixture was allowed to stir for a further 18hours. The reaction mixture was applied to a SCX ion cartridge (Varianbond-elute, 10 g) and washed with methanol and then a mixture of 0.880ammonia:methanol (1:9). The combined basic fractions were concentratedin vacuo to afford the title compound (E196). MS (ES+) m/e 378 [M+H]⁺.

Examples 197-202

Examples 197-202 (E197-E202) were prepared from6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxylicacid (E196b) and the appropriate amine indicated in the table using ananalogous method to that described for Example 196 (E196):

LC/MS Example Amine (M + H⁺⁾ 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-Isopropylamine 380 benzazepin-7-yl)oxy]-N-(1-methylethyl)-3-pyridinecarboxamide (E197) 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-Ethylamine 366 benzazepin-7-yl)oxy]-N-ethyl-3- pyridinecarboxamide(E198) N-Cyclobutyl-6-[(3-cyclobutyl-2,3,4,5- Cyclobutylamine 392tetrahydro-1H-3-benzazepin-7-yl)oxy]-3- pyridinecarboxamide (E199)6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Tetrahydro-2H-pyran-4- 422benzazepin-7-yl)oxy]-N-(tetrahydro-2H-pyran-4- amineyl)-3-pyridinecarboxamide (E200)6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Diethylamine 394benzazepin-7-yl)oxy]-N,N-diethyl-3- pyridinecarboxamide (E201)6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- [2-(Methyloxy)ethyl]amine 396benzazepin-7-yl)oxy]-N-[2-(methyloxy)ethyl]-3- pyridinecarboxamide(E202)

Examples 203-205

Examples 203-205 (E203-205) were prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and theappropriate aromatic iodide indicated in the table using an analogousmethod to that described for Example 128 (E128):

LC/MS Example Iodide (M + H⁺⁾ 4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-4-Iodo-N-ethyl-N-[2- 423 benzazepin-7-yl)oxy]-N-ethyl-N-[2-(methyloxy)ethyl]benzamide (methyloxy)ethyl]benzamide (E203) (D50)4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- 4-Iodo-N-methylbenzamide 351benzazepin-7-yl)oxy]-N-methylbenzamide (D51) (E204)3-Cyclobutyl-7-(3-pyridinyloxy)-2,3,4,5- 3-Iodopyridine 294tetrahydro-1H-3-benzazepine (E205)

Example 2065-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyridinecarbonitrile(E206)

The title compound (E206) was prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) and5-iodo-2-pyridinecarbonitrile (Biochemical Journal, 1973, 131(4), 625)according to the method outlined for E177a; MS (ES+) m/e 320 [M+H]⁺.

Examples 207-208

Examples 207-208 (E207-208) were prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and theappropriate aromatic chloride indicated in the table using an analogousmethod to that described for Example 100 (E100):

LC/MS Example Chloride (M + H⁺⁾3-Cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]- 2-Chloro-5- 4212,3,4,5-tetrahydro-1H-3-benzazepine (E207) iodopyridine3-Cyclobutyl-7-[(5-nitro-2-pyridinyl)oxy]- 2-Chloro-5- 3402,3,4,5-tetrahydro-1H-3-benzazepine (E208) nitropyridine

Example 209N-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}acetamide(E209)

Iron filings (451 mg, 8.07 mmol) were added to a stirred solution of3-cyclobutyl-7-[(5-nitro-2-pyridinyl)oxy)]-2,3,4,5-tetrahydro-1H-3-benzazepine(E208) (550 mg, 1.62 mmol) in a mixture of acetic acid:acetic anhydridesolution (1:1, 10 ml) and heated at 80° C. for 16 hours. The reactionmixture was cooled, poured onto ice and taken to pH 8 with sodiumbicarbonate. The product was extracted into ethyl acetate and theorganic extract was then washed with brine and dried over sodiumsulphate. The residue was purified by column chromatography eluting witha mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) toafford the title compound (E209). MS (ES+) m/e 352 [M+H]⁺.

Example 210a3-Cyclobutyl-7-[(5-nitro-1,3-thiazol-2-yl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E210a)

Sodium hydride (60% disp. in mineral oil, 150 mg, 3.66 mmol) was addedto a stirred solution of3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (530 mg,2.43 mmol) in dimethylformamide (10 ml) at 5° C. After 0.5 hours asolution of 2-bromo-5-nitro-1,3-thiazole (1.0 g, 4.78 mmol) indimethylformamide (5 ml) was added and the reaction mixture was allowedto warm to room temperature and stir for 2 hours. The reaction mixturewas diluted with ethyl acetate and the organic layer was washed withwater, brine, dried (sodium sulfate) and concentrated in vacuo.Purification by column chromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.25:2.25:97.5) afforded the titlecompound (E210a); MS (ES+) m/e 346 [M+H]⁺.

Example 210N-{2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1,3-thiazol-5-yl}acetamide(E210)

Iron powder (162 mg, 2.9 mmol) was added to a stirred solution of3-cyclobutyl-7-[(5-nitro-1,3-thiazol-2-yl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E210a) (162 mg, 0.47 mmol) in acetic acid (1 ml) and acetic anhydride(1 ml). The reaction mixture was stirred at 80° C. for 16 hours thencooled and poured onto ice. The solution was basified to pH 8 (sodiumbicarbonate) and the resulting mixture was extracted with ethyl acetate.The organic layer was washed with brine and dried (sodium sulfate).Concentration in vacuo and subsequent purification of the resultingresidue by column chromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.3:2.7:97) afforded the titlecompound (E210). MS (ES+) m/e 358 [M+H]⁺.

Example 2113-Cyclobutyl-7-[(5-nitro-2-thienyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E211)

A mixture of 2-bromo-5-nitrothiophene (478 mg, 2.3 mmol),3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (500 mg, 2.3mmol) and potassium carbonate (765 mg, 5.5 mmol) in dimethylformamide(10 ml) was stirred at 80° C. for 16 hours. The reaction mixture wascooled, diluted with ethyl acetate and washed with water, brine anddried (sodium sulfate). Concentration in vacuo and purification of theresulting residue by column chromatography 0.880ammonia:methanol:dichloromethane (1:8:300) afforded the title compound(E211); MS (ES+) m/e 345 [M+H]⁺.

Example 212N-{5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-thienyl}acetamide(E212)

Example 212 (E212) was prepared from3-cyclobutyl-7-[(5-nitro-2-thienyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E211) using an analogous method to that described for Example 210(E210); MS (ES+) m/e 357 [M+H]⁺.

Example 213a3-Cyclobutyl-7-{[6-(methyloxy)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E213a)

Title compound was prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and5-bromo-2-methoxypyridine using the protocol outlined for Example 128(E128); MS (ES+) m/e 325 [M+H]⁺.

Example 2135-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2(1H)-pyridinone(E213)

3-Cyclobutyl-7-{[6-(methyloxy)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E213a) (69 mg, 0.21 mmol) was dissolved in a solution of ethanolsaturated with hydrogen chloride (5 ml). The reaction mixture wasstirred at reflux for 18 hours, cooled and concentrated in vacuo.Purification of the resulting residue by column chromatography elutingwith a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90)afforded the title compound (E213). MS (ES+) m/e 311 [M+H]⁺.

Example 2141-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}ethanone(E214)

Example 214 (E214) was prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and1-(6-chloropyridin-3-yl)ethanone using the method described for Example100 (E100); MS (ES+) m/e 337 [M+H]⁺.

Example 2153-Cyclobutyl-7-{[5-(1H-pyrazol-5-yl)-2-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E215)

A mixture of(2E)-1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-3-(dimethylamino)-2-propen-1-one(D53) (195 mg, 0.5 mmol) and hydrazine hydrate (0.4 ml) in methanol (3ml) was heated at reflux for 24 hours. The reaction mixture was cooledand applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g)and washed with methanol and then a mixture of 0.880 ammonia/methanol(1:9). The combined basic fractions were concentrated in vacuo and theresulting residue purified by column chromatography eluting with amixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford thetitle compound (E215). MS (ES+) m/e 361 [M+H]⁺.

Example 2163-Cyclobutyl-7-{[5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E216)

A mixture of triethylorthoacetate (3 ml) and6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarbohydrazide(D54) (185 mg, 0.52 mmol) was heated at reflux for 16 hours. Thereaction mixture was concentrated and the resulting residue was purifiedby column chromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.1:5:95) to afford the title compound(E216). MS (ES+) m/e 377 [M+H]⁺.

Example 2171-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone(E217)

A mixture of3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) (252 mg, 0.6 mmol), 2-pyrrolidinone (153 mg, 1.8 mmol), potassiumcarbonate (83 mg, 0.6 mmol), copper powder (126 mg, 1.2 mmol) wereheated in a microwave reactor at 150° C. for 1 minute. The reactionmixture was diluted with 2-pyrrolidinone (1 g, 12 mmol) and heated for afurther 20 minutes at 200° C. The reaction mixture was cooled andapplied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) andwashed with methanol and then a mixture of 0.880 ammonia/methanol. Thecombined basic fractions were concentrated in vacuo and the resultingresidue purified by column chromatography eluting with a mixture of0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the titlecompound (E217). MS (ES+) m/e 378 [M+H]⁺.

Example 2181-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-piperidinone(E218)

Example 218 (E218) was prepared from3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) and 2-piperidinone using the method described for Example 217(E217); MS (ES+) m/e 392 [M+H]⁺.

Example 2191-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-azetidinone(E219)

Cesium carbonate (678 mg, 1.04 mmol) was added to a solution of2-azetidinone (308 mg, 4.3 mmol) in dioxane (1 ml). The mixture washeated in a microwave reactor at 150° C. for 1 minute then a mixture of3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) (294 mg, 0.7 mmol), trans-1,2-diaminocyclohexane (0.02 ml) andcopper (I) iodide (126 mg, 1.2 mmol) were added and the resultingmixture was heated in microwave reactor at 180° C. for 1 hour. Thereaction mixture was cooled and applied to a SCX cartridge (Varianbond-elute, 10 g) and washed with methanol and then a mixture of 0.880ammonia:methanol (1:9). The combined basic fractions were concentratedin vacuo and the resulting residue purified by column chromatography(0.5:2.5:97.5) to afford the title compound (E219). MS (ES+) m/e 364[M+H]⁺.

Example 2203-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-1,3-oxazolidin-2-one(E220)

Example 220 (E220) was prepared from3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) and 1,3-oxazolidin-2-one using the method described for Example219 (E219); MS (ES+) m/e 380 [M+H]⁺.

Example 2213-Cyclobutyl-7-{[5-(1H-pyrazol-1-yl)-2-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E221)

A mixture of3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) (294 mg, 0.7 mmol), pyrazole (58 mg, 0.84 mmol), cesium carbonate(479 mg, 1.5 mmol), copper (I) iodide (7 mg, 0.04 mmol) and 1,10phenanthroline (13 mg, 0.07 mmol) in dioxane (2 ml) were heated in amicrowave reactor at 180° C. for 20 minutes. The reaction mixture wasdiluted with ethyl acetate and washed with a saturated solution ofammonium chloride, water, brine and dried (magnesium sulfate). Theorganic layer was filtered, concentrated in vacuo and the resultingresidue was purified by column chromatography eluting with a mixture of0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the titlecompound (E221); MS (ES+) m/e 361 [M+H]⁺.

Example 2223-Cyclobutyl-7-{[5-(3,5-dimethyl-4-isoxazolyl)-2-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E222)

A mixture of3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) (252 mg, 0.6 mmol), 3,5 dimethyl-4-isoxazoyl boronic acid (168mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) in 2M sodiumcarbonate solution (5 ml) and ethylene glycol dimethyl ether (10 ml) wasstirred at reflux for 14 hours. The reaction mixture was diluted withethyl acetate and washed with a saturated solution of sodiumbicarbonate, water, brine and dried (sodium sulfate). The organic layerwas filtered, concentrated in vacuo and the resulting residue waspurified by column chromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the titlecompound (E222); MS (ES+) m/e 390 [M+H]⁺.

Example 2236-[(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide(E223)

N-Methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide(D40) (150 mg, 0.5 mmol) was dissolved in 2.5% acetic acid in methanol(5 ml) and treated dropwise with cyclopentanone (0.09 ml, 1 mmol). Themixture was stirred for 30 minutes and then(polystyrylmethyl)trimethylammonium cyanoborohydride (2.04 mmol/g, 490mg, 0.1 mmol) was added. The reaction mixture was stirred at roomtemperature for 14 hours, applied to a SCX cartridge (Varian bond-elute,10 g) and washed with methanol and then a mixture of 0.880ammonia/methanol. The combined basic fractions were concentrated invacuo and the resulting residue purified by column chromatographyeluting with a mixture of 0.880 ammonia:methanol:dichloromethane(0.25:2.25:97.5) to afford the title compound (E223). MS (ES+) m/e 366[M+H]⁺.

Example 224N-Methyl-6-{[3-(2-methylcyclopentyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]oxy}-3-pyridinecarboxamide(E224)

Example 224 (E224) was prepared fromN-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide(D40) and 2-methyl cyclopentanone using the method described for Example223; MS (ES+) m/e 380 [M+H]⁺.

Example 2256-[(3-Cyclobutyl-8-iodo-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide(E225)

N-Methyl-6-(8-iodo-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide(D43) (423 mg, 1.0 mmol) was dissolved in 2.5% acetic acid in methanol(5 ml) and treated dropwise with cyclobutanone (0.11 ml, 1.5 mmol). Themixture was stirred for 30 minutes and then(polystyrylmethyl)trimethylammonium cyanoborohydride (2.0 mmol/g, 1 g, 2mmol) was added. The reaction mixture was stirred at room temperaturefor 18 hours, applied to a SCX ion exchange cartridge (Varianbond-elute, 10 g) and washed with methanol and then a mixture of 0.880ammonia:methanol (1:9). The combined basic fractions were concentratedin vacuo and the resulting residue purified by column chromatographyeluting with a mixture of 0.880 ammonia:methanol:dichloromethane(0.5:2.25:97.5) to afford the title compound (E225). MS (ES+) m/e 478[M+H]⁺.

Example 226 3-Cyclobutyl-7-iodo-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E226)

Example 226 (E226) was prepared from7-iodo-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (D45)and cyclobutanone using the method described for Example 225 (E225); MS(ES+) m/e 434 [M+H]⁺.

Example 2273-Cyclobutyl-7-{[6-methyl-4-(methyloxy)-2-quinolinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E227)

A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3)(58 mg, 0.267 mmol), 2-chloro-6-methyl-4-(methyloxy)quinoline (WO99/55677) (56 mg, 0.027 mmol) and cesium carbonate (260 mg, 0.801 mmol)in dry DMF (3 ml) was heated at 150° C. for 2×30 mins. (300 W) in amicrowave reactor. The cooled reaction mixture was partitioned betweenethyl acetate (3×20 ml) and water (30 ml). The combined organic layerswere washed with brine (2×30 ml), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the resulting residue by columnchromatography on silica gel, eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the titlecompound (E227); MS (ES+) m/e 389 [M+H]⁺.

Examples 228-230

Examples 228-230 (E228-E230) were prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and theappropriate aromatic halide indicated in the table using an analogousmethod to that described for Example 227:

Aromatic LC/MS Example chloride (M + H⁺⁾3-Cyclobutyl-7-{[4-(methyloxy)-1,7- 2-Chloro-4- 376naphthyridin-2-yl]oxy}-2,3,4,5- (methyloxy)-1,7-tetrahydro-1H-3-benzazepine naphthyridine (E228)3-Cyclobutyl-7-(1,5-naphthyridin-2- 2-Bromo-1,5- 346yloxy)-2,3,4,5-tetrahydro-1H-3- naphthyridine benzazepine (E229) (J. W.Henk, J.Org.Chem., 1982, 47(9), 1673-1677)N-{7-[(3-Cyclobutyl-2,3,4,5-tetrahydro- N-(7-Chloro-6- 4171H-3-benzazepin-7-yl)oxy]-6-methyl- methyl-1,8-1,8-naphthyridin-2-yl}acetamide naphthyridin-2- (E230) yl)acetamide (S.Carboni, Gazz. Chim. Ital., 1966, 96(11), 1456-1469)

Example 231 Dimethyl6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate(E231)

A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3)(1.5 g), dimethyl 6-chloro-2,3-pyridinedicarboxylate (1.58 g; KenjiNiiyama et al. Bioorg. Med. Chem. Lett. 12, 21, 2002, 3041-3054) andcesium carbonate (4.4 g) in dry DMF (30 ml) was heated at 80° C. for 3h. The cooled mixture was partitioned between water (20 ml) and ethylacetate (3×100 ml), the combined organic extracts were washed with brine(2×100 ml) and dried (Na₂SO₄). The solvent was evaporated to give an oilwhich was purified by column chromatography eluting with a mixture of0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the titlecompound (E231); MS (ES+) m/e 411 [M+H]⁺.

Example 232 Disodium6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate(E232)

Sodium hydroxide (0.66 g) in water (3 ml) was added to a solution ofdimethyl6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate(E231) (1.69 g, 4.12 mmol) in ethanol (20 ml) at room temperature. Themixture was vigorously stirred at room temperature for 4 h and theresulting precipitate filtered off to give the title compound as acolourless solid (E232); MS (ES+) m/e 383 [M+H]⁺.

Example 2332-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione(E233)

A suspension of disodium6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate(E232) (0.2 g, 0.52 mmol) in acetic anhydride (2 ml) was stirred andheated at 120° C. for 20 mins. The cooled mixture was concentrated invacuo and acetamide (0.1 g) added to the residue and the mixture heatedat 160° C. for 0.5 h. The cooled mixture was then purified by columnchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.5:4.5:95). The resulting pale yellowsolid was triturated with ether (5 ml) and filtered to give the titlecompound (E233); MS (ES+) m/e 364 [M+H]⁺.

Example 2342-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(E234)

Magnesium perchlorate (0.89 g) was added to a solution of2-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione(E233) (0.72 g, 1.98 mmol) in a mixture of chloroform:methanol (1:1; 20ml) at 0° C. under argon. Sodium borohydride (113 mg) was added and themixture stirred at for 0.5 h. The mixture was adjusted to pH 2 with HCl(2M), stirred for an additional 0.5 h, then taken to pH 11 with sodiumhydroxide (2N). The mixture was then extracted with dichloromethane andthe combined organic extracts dried (Na⁻²SO₄) and evaporated. Theresidue was purified by column chromatography eluting with a mixture of0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the titlecompound (E234); MS (ES+) m/e 366 [M+H]⁺.

Example 2352-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(E235)

A mixture of2-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(E234) (90 mg, 0.25 mmol) and triethylsilane (0.1 ml) in trifluoroaceticacid (0.1 ml) was vigorously stirred at room temperature for 1 h. Themixture was concentrated in vacuo and the residue purified by columnchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (1:9:90); MS (ES+) m/e 350 [M+H]⁺.

Example 2366-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinamine(E236)

3-Cyclobutyl-7-[(5-nitro-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E208) (100 mg, 0.29 mmol) was dissolved in ethanol (10 ml). Palladium(20 mg, 10% on charcoal paste) was added and the reaction mixture wasstirred at room temperature under hydrogen (1 atmosphere) for 12 hours.The reaction mixture was filtered through celite and the filtrateconcentrated in vacuo to afford the title compound (E236); MS (ES+) m/e310 [M+H]⁺.

Example 237 Morpholine-4-carboxylicacid[6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy-pyridin-3-yl-amide(E237)

Morpholine-4-carbonyl chloride (0.15 ml, 1.38 mmol) was added to astirred solution of6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinamine(E236) (77 mg, 0.25 mmol) and triethylamine (0.04 ml, 0.30 mmol) indichloromethane (5 ml) at 0° C. The reaction mixture was warmed to roomtemperature and allowed to stir for 24 hours. The reaction mixture wasapplied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) andwashed with methanol and then a mixture of 0.880 ammonia:methanol (1:9).The combined basic fractions were concentrated in vacuo and theresulting residue purified by column chromatography eluting with amixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to affordthe title compound; MS (ES+) m/e 423 [M+H]⁺.

Examples 238-240

Examples 238-240 were prepared from6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinamine(E236) and the appropriate carbonyl chloride or acid chloride indicatedin the table using an analogous method to that described for Example 237(E237):

Carbonyl Chloride/Acid LC/MS Example Chloride (M + H⁺⁾Piperidine-1-carboxylic acid[6- Piperidine-1-carbonyl 421(3-cyclobutyl-2,3,4,5-tetrahydro- chloride 1H-benzo[d]azepin-7-yloxy-pyridin-3-yl]-amide (E238) Pyrrolidine-1-carboxylic acid[6-Pyrrolidine-1-carbonyl 407 (3-cyclobutyl-2,3,4,5-tetrahydro- chloride1H-benzo[d]azepin-7-yloxy)- pyridin-3-yl]-amide (E239)N-[6-(3-Cyclobutyl-2,3,4,5- Isobutyryl chloride 380tetrahydro-1H-benzo[d]azepin- 7-yloxy)-pyridin-3-yl] isobutyramide(E240)

Example 241 Tetrahydro-pyran-4-carboxylic acid[6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-3-yl]-amide(E241)

Tetrahydro-pyran-4-carboxylic acid (252 mg, 1.94 mmol), 1-hydroxybenzotriazole hydrate (262 mg, 1.94 mmol) and N-cyclohexylcarbodiimideN′-methyl polystyrene (1.7 mmol/g, 2.3 g, 3.88 mmol) were stirred atroom temperature in dichloromethane (10 ml) for 15 minutes.6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinamine(E236) (300 mg, 0.97 mmol) was added and stirring continued for 16hours. The reaction mixture was applied to a SCX ion exchange cartridge(Varian bond-elute, 5 g) and washed with methanol and then a mixture of0.880 ammonia/methanol. The combined basic fractions were concentratedin vacuo and the resulting residue was purified by column chromatographyeluting with a mixture of 0.880 ammonia:methanol:dichloromethane(0.5:4.5:95) to afford the title product (E241); MS (ES+) m/e 422[M+H]⁺.

Example 2423-Cyclobutyl-7-[5-(4,6-dimethoxy-pyrimidin-2-yl)-pyridin-2-yloxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E242)

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (125 mg,0.58 mmol), 2-(6-chloro-pyridin-3-yl)-4,6-dimethoxy-pyrimidine (145 mg,0.58 mmol), calcium carbonate (720 mg, 2.2 mmol) and dimethylformamide(4 ml) were heated in a microwave reactor at 180° C. for 900 seconds at300 W. The mixture was diluted with ethyl acetate, washed with water,then brine and dried over sodium sulphate. The residue was purified bycolumn chromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the titleproduct. MS (ES+) m/e 433 [M+H]⁺.

Examples 243-249

Examples 243-249 (E243-E249) were prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and the arylchloride indicated in the table using an analogous method to thatdescribed for Example 242 (E242).

LC/MS Example Aryl Chloride (M + H⁺⁾ 3-Cyclobutyl-7-[5-(4-2-(6-Chloro-pyridin-3-yl)- 450 methanesulfonyl-phenyl)-5-methanesulfonyl-pyrazine pyrazine-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E243) N-{4-[5-(3-Cyclobutyl-2,3,4,5-N-[4-(5-Chloro-pyrazin-2- 429 tetrahydro-1H-benzo[d]azepin-yl)-phenyl]-acetamide 7-yloxy)-pyrazin-2-yl]-phenyl}- acetamide (E244)3-Cyclobutyl-7-(3,5-dimethyl- 2-Chloro-3,5-dimethyl- 323pyridin-2-yloxy)-2,3,4,5- pyridine tetrahydro-1H-benzo[d]azepine (E245)3-Cyclobutyl-7-[5-(morpholine- 4-(6-Chloro-pyridine-3- 4444-sulfonyl)-pyridin-2-yloxy]- sulfonyl)-morpholine2,3,4,5-tetrahydro-1H- benzo[d]azepine (E246) 3-Cyclobutyl-7-(2-methyl-7-Chloro-2-methyl- 349 furo[2,3-c]pyridin-7-yloxy)- furo[2,3-c]pyridine2,3,4,5-tetrahydro-1H- benzo[d]azepine (E247) 2-(3-Cyclobutyl-2,3,4,5-2-Chloro-4-ethoxy- 364 tetrahydro-1H-benzo[d]azepin- nicotinonitrile7-yloxy)-4-ethoxy-nicotinonitrile (E248) 6-(3-Cyclobutyl-2,3,4,5-6-Chloro-2-methyl- 334 tetrahydro-11H-benzo[d] nicotinonitrileazepin-7-yloxy)-2-methyl- nicotinonitrile (E249)

Example 2501-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-5-methyl-2-pyrrolidinone(E250)

3-Cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) (294 mg, 0.7 mmol) 1,10 phenanthroline (38 mg, 0.2 mmol),5-methyl-2-pyrrolidinone (139 mg 1.4 mmol) were dissolved in dioxane (2ml). Copper(I) Iodide (39 mg, 0.2 mmol) and caesium carbonate (479 mg,1.5 mmol) were added and the mixture heated in a microwave reactor at175° C. for 15 minutes. The mixture was cooled and filtered throughcelite, washing through with dichloromethane. The filtrate wasconcentrated in vacuo and the crude material purified by columnchromatography, eluting with dichloromethane through to a mixture of0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the titlecompound (137 mg); MS (ES+) m/e 392 [M+H]⁺.

Example 2511-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-3-methyl-2-imidazolidine(E251)

3-Cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) (294 mg 0.7 mmol), 1-methyl-2-imidazolidinone (90 mg, 0.9 mmol)caesium carbonate (364 mg 1.1 mmol) xantphos (12 mg, 0.02 mmol), weresuspended in toluene (10 ml). tris(dibenzylideneacetone)dipalladium(0)(6 mg, 0.007 mmol) was added and the mixture heated at reflux overnight.The reaction was then applied directly on to SCX ion exchange cartridge(Varian, 5 g) and washed with methanol then a mixture of 0.880ammonia:methanol (1:9). The basic fractions were reduced and the crudematerial purified by automated reverse phase chromatography to affordthe title product (104 mg); MS (ES+) m/e 393 [M+H]⁺.

Example 252(4R)-1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-4-hydroxy-2-pyrrolidinone(E252)

Example 252 (E252) was prepared from3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) and(4R)-4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-pyrrolidinone(Tetrahedron, 2000, 56(39), 7705-7713) using the method described inE251; MS (ES+) m/e 394 [M+H]⁺.

Example 253N-Methyl-6-{[3-(3-methylcyclopentyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]oxy}-3-pyridinecarboxamide(E253)

Example 253 (E253) was prepared fromn-methyl-6-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-3-pyridinecarboxamide(D40) and 3-methyl cyclopentanone using the method described for Example223; MS (ES+) m/e 380 [M+H]⁺.

Example 2545-[(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide(E254)

Example 254 (E254) was prepared fromn-methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide(D49) and cyclopentanone using the method described for Example 223; MS(ES+) m/e 367 [M+H]⁺.

Example 255N-Methyl-5-{[3-(3-methylcyclopentyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]oxy}-2-pyrazinecarboxamide(E255)

Example 255 (E255) was prepared fromN-methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide(D49) and 3-methyl cyclopentanone using the method described for Example223; MS (ES+) m/e 381 [M+H]⁺.

Example 2561-{3-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinyl}-2-pyrrolidinone(E256)

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (103 mg,0.47 mmol) was dissolved in dry dimethylformamide (3 ml), cooled to 0°C. and treated with sodium hydride (60% in mineral oil, 20 mg, 0.49mmol). The mixture was allowed to warm to room temperature over 40minutes. A solution of 1-(3-chloro-2-pyrazinyl)-2-pyrrolidinone (D46)(103 mg, 0.52 mmol) in dry dimethylformamide (1 ml) was added and themixture stirred at room temperature for 2 hours and heated at 80° C. for2.5 hours. The mixture was allowed to cool to room temperature andapplied to a SCX column and washed with methanol then a mixture of 0.880ammonia/methanol (1:9). The basic fractions were combined andconcentrated in vacuo and resulting residue was purified by columnchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the titlecompound (86 mg); MS (ES+) m/e 379 [M+H]⁺.

Example 2577-[(5-Chloro-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine(E257)

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (184 mg,0.85 mmol) was dissolved in dry dimethylformamide (3 ml), cooled to 0°C. and treated with sodium hydride (60% in mineral oil, 36 mg, 0.89mmol). The mixture was allowed to warm to room temperature over 30minutes. A solution of 2,5-dichloropyrazine (D47) (139 mg, 0.94 mmol) indry dimethylformamide (1 ml) was added and the mixture stirred at roomtemperature for 5 hours. The mixture was applied to a SCX column andwashed with methanol then a mixture of 0.880 ammonia/methanol (1:9). Thebasic fractions were combined and concentrated in vacuo to afford thetitle compound (268 mg); MS (ES+) m/e 330 [M+H]⁺.

Example 2581-{5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinyl}-2-pyrrolidinone(E258)

7-[(5-Chloro-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine(E257) (132 mg, 0.40 mmol), pyrrolidinone (0.06 ml, 0.80 mmol),potassium carbonate (200 mg, 1.45 mmol), copper (I) iodide (23 mg, 0.12mmol) and N,N′-dimethylethylenediamine (0.01 ml, 0.12 mmol) were addedtogether in dry dioxane (3 ml) and heated in a microwave reactor at 175°C. for 30 minutes. The mixture was diluted with methanol and applied toa SCX column and washed with methanol then a mixture of 0.880ammonia/methanol (1:9). The basic fractions were combined andconcentrated in vacuo and the resulting residue was purified by columnchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the titlecompound (64 mg); MS (ES+) m/e 379 [M+H]⁺.

Example 2597-[(5-Bromo-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine(E259)

The title compound was prepared from3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and2,5-dibromopyrazine (D48) using the method of Example 257 (E257); MS(ES+) m/e 375 [M+H]⁺.

Example 2603-{5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinyl}-1,3-oxazolidin-2-one(E260)

The title compound was prepared from7-[(5-bromo-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine(E259) and oxazolidinone using the method of Example 258 (E258); MS(ES+) m/e 381 [M+H]⁺.

Example 2613-Cyclobutyl-7-[5-(1,1-dioxo-2-isothiazolidin-2-yl)-pyridin-2-yloxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E261)

3-Cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) (200 mg, 0.48 mmol), isothiazolidine 1,1-dioxide (116 mg, 0.96mmol), (Evans, Brian J.; Takahashi Doi, Joyce; Musker, W. Kenneth; J.Org. Chem.; 55; 9; 1990; 2580-2586) potassium carbonate (238 mg, 1.73mmol), copper (I) iodide (27 mg, 0.14 mmol) andN,N-dimethylethylenediamine (0.02 ml, 0.14 mmol) were added together indry dioxane (3 ml) and heated in a microwave reactor at 140° C. for 20minutes. The mixture was diluted with methanol and applied to a SCXcolumn eluting with methanol and then a mixture of 0.880ammonia/methanol (1:9). The basic fractions were combined andconcentrated in vacuo. The resulting residue was purified by columnchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the titlecompound (145 mg); MS (ES+) m/e 414 [M+H]⁺.

Example 2621-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-imidazolidinone(E262)

The title compound was prepared from3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E207) and 2-imidazolidinone using the method of Example 261; MS (ES+)m/e 379 [M+H]⁺.

Example 2635-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxamide(E263)

5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxylicacid (E123a) (168 mg, 0.47 mmol) was dissolved in dry dimethylformamide(5 ml), treated with 1,1′-carbonyldiimidazole (230 mg, 1.42 mmol) andthe resulting mixture stirred at room temperature for 1.5 hours. Themixture was treated with 0.880 ammonia (0.14 ml, 2.84 mmol) and stirredfor 4 hours. The reaction mixture was concentrated in vacuo and theresulting residue purified by column chromatography eluting with amixture of (0.5:4.5:95) to afford the title compound; MS (ES+) m/e 339[M+H]⁺.

Example 2644-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-(methyloxy)benzamide(E264)

Step 1: 1,1-Dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

1,1-Dimethylethyl7-{[(trifluoromethyl)sulfonyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(2.0 g, 5.06 mmol) (Bioorg. Med. Chem. Lett.; 10; 22; 2000; 2553-2556),bis(pinacolato)diboron (1.41 g, 5.57 mmol),1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) complex (0.22g, 0.30 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.17 g, 0.30 mmol)and potassium acetate (1.49 g, 15.2 mmol) were added together in drydioxane and the resulting mixture heated at 80° C. for 3 hours. Themixture was allowed to cool to room temperature, diluted with ethylacetate and washed with water and brine. The organic portion was driedunder magnesium sulfate and evaporated in vacuo. The resulting residuewas purified by column chromatography eluting with a mixture of ethylacetate:pentane (1:9) to afford the title compound (1.60 g); MS (ES+)m/e 274 [(M+H)—CO₂ ^(t)Bu]⁺.

Step 2:(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronicacid

1,1-Dimethylethyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E264, Step 1) (1.60 g, 4.29 mmol) was dissolved in acetone (25 ml),treated with sodium periodate (2.75 g, 12.9 mmol), ammonium acetate(0.73 g, 9.44 mmol) and water (25 ml) and the resulting mixture wasstirred for 18 hours at room temperature. The acetone was removed byevaporation in vacuo and the remaining water layer was extracted withethyl acetate and dichloromethane. The organic layers were combined,dried under magnesium sulfate and evaporated in vacuo to give the titlecompound (1.06 g); MS (ES+) m/e 192 [(M+H)—CO₂ ^(t)Bu]⁺.

Step 3: 1,1-Dimethylethyl7-({2-(methyloxy)-4-[(methyloxy)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronicacid (E264, Step 2) (500 mg, 1.72 mmol) was dissolved in drydichloromethane (15 ml) and treated sequentially with methyl vanillate(313 mg, 1.72 mmol), molecular sieves (4 A, 1.0 g), copper acetate (467mg, 2.58 mmol) and triethylamine (1.20 ml, 8.60 mmol) and the resultingmixture was stirred at room temperature for 18 hours. The mixture wasdiluted with dichloromethane, filtered through celite and evaporated invacuo. The residue was dissolved in ethyl acetate and washed withsaturated sodium bicarbonate solution. The organic portion was driedunder magnesium sulfate and evaporated in vacuo. The resulting residuewas purified by column chromatography eluting with a mixture of(0.1:9.9) to afford the title compound (240 mg). MS (ES+) m/e 328[(M+H)—CO₂ ^(t)Bu]⁺.

Step 4:4-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-(methyloxy)benzoicacid

1,1-Dimethylethyl7-({2-(methyloxy)-4-[(methyloxy)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E264, Step 3) (240 mg, 0.56 mmol) was dissolved in ethanol (2 ml),treated with 2M sodium hydroxide (1 ml) and the resulting mixture wasstirred for 1.5 hours. The mixture was acidified with 2M hydrochloricacid and extracted with ethyl acetate. The ethyl acetate layers werecombined, dried under magnesium sulfate and evaporated in vacuo toafford the title compound (0.15 g); MS (ES+) m/e 314 [(M+H)—CO₂^(t)Bu]⁺.

Step 5: 1,1-Dimethylethyl7-{[4-[(methylamino)carbonyl]-2-(methyloxy)phenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

4-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-(methyloxy)benzoicacid (E264, Step 4) (145 mg, 0.35 mmol) was dissolved in drydimethylformamide (5 ml), treated with 1,1′-carbonyldiimidazole (85 mg,0.53 mmol) and the resulting mixture stirred at room temperature for 3hours. The mixture was treated with methylamine (0.53 ml, 1.05 mmol, 2Min THF) and stirred for 4 hours. The reaction mixture was concentratedin vacuo and the resulting residue purified by column chromatography(1:1 ethyl acetate:pentane) to afford the title compound (0.10 g); MS(ES+) m/e 327 [(M+H)—CO₂ ^(t)Bu]⁺.

Step 6:N-Methyl-3-(methyloxy)-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide

1,1-Dimethylethyl7-{[4-[(methylamino)carbonyl]-2-(methyloxy)phenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E264, Step 5) (100 mg, 0.23 mmol) was dissolved in dry dichloromethane(2 ml), treated with trifluoroacetic acid (1 ml) and the resultingmixture was stirred at room temperature for 2 hours. The solvent wasremoved in vacuo and the residue dissolved in methanol and applied to aSCX column eluting with methanol and then a mixture of 0.880ammonia:methanol (1:9). The basic fractions were combined andconcentrated in vacuo to afford the title compound (78 mg); MS (ES+) m/e327 [M+H]⁺.

Step 7:4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-(methyloxy)benzamide

N-Methyl-3-(methyloxy)-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide(E264, Step 6) (78 mg, 0.24 mmol) was dissolved in dry dichloromethane(5 ml), treated with cyclobutanone (0.04 ml, 0.48 mmol) and acetic acid(1 drop) and the resulting mixture stirred for 15 minutes. Sodiumtriacetoxyborohydride (102 mg, 0.48 mmol) was added and the mixturestirred for 30 minutes. The mixture was diluted with methanol andapplied to a SCX column eluting with methanol and then a mixture of0.880 ammonia/methanol (1:9). The basic fractions were combined andconcentrated in vacuo. The resulting residue was purified by columnchromatography eluting with a mixture ofammonia:methanol:dichloromethane (0.5:4.5:95.880) to afford the titlecompound (20 mg); MS (ES+) m/e 381 [M+H]⁺.

Example 2652-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]benzonitrile(E265)

3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (300 mg,1.38 mmol) was dissolved in pyridine (10 ml), cooled in an ice bath andtreated with sodium hydride (60% in mineral oil) (66 mg, 1.66 mmol)under argon. The resulting mixture was stirred for 5 minutes, treatedwith copper (I) bromide (277 mg, 1.93 mmol) and allowed to warm to roomtemperature over 30 minutes. A solution of 2-iodobenzonitrile (948 mg,4.14 mmol) in pyridine (2 ml) was added and the mixture heated underreflux for 2.5 hours. The mixture was allowed to cool to roomtemperature and the solvent removed in vacuo. The resulting residue waspurified by column chromatography eluting with a mixture ofammonia:methanol:dichloromethane (0.2:1.8:98) to afford the titlecompound (180 mg); MS (ES+) m/e 319 [M+H]⁺.

Example 2663-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-4-(methyloxy)benzamide(E266)

Step 1: 1,1-Dimethylethyl7-({2-(methyloxy)-5-[(methyloxy)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

The title compound was prepared from(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronicacid (E264, Step 2) and methyl-3-hydroxy-4-methoxybenzoate using themethod of Example 264 Step 3; MS (ES+) m/e 328 [(M+H)—CO₂ ^(t)Bu]⁺.

Step 2:3-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-4-(methyloxy)benzoicacid

The title compound was prepared from 1,1-dimethylethyl7-({2-(methyloxy)-5-[(methyloxy)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E266, Step 1) using the method of Example 264 Step 4; MS (ES+) m/e 314[(M+H)—CO₂ ^(t)Bu]⁺.

Step 3: 1,1-Dimethylethyl7-{[5-[(methylamino)carbonyl]-2-(methyloxy)phenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

The title compound was prepared from3-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-4-(methyloxy)benzoicacid (E266, Step 2) and methylamine using the method of Example 264,Step 5; MS (ES+) m/e 327 [(M+H)—CO₂ ^(t)Bu]⁺.

Step 4:N-Methyl-4-(methyloxy)-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide

The title compound was prepared from 1,1-dimethylethyl7-{[5-[(methylamino)carbonyl]-2-(methyloxy)phenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E266, Step 3) using the method of Example 264 Step 6; MS (ES+) m/e 327[M+H]⁺.

Step 5:3-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-4-(methyloxy)benzamide

The title compound was prepared fromN-methyl-4-(methyloxy)-3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide(E266, Step 4), using the method of Example 264 Step 7; MS (ES+) m/e 381[M+H]⁺.

Example 2673-Chloro-4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide(E267)

Step 1: 1,1-Dimethylethyl7-({2-chloro-4-[(methyloxy)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

The title compound was prepared from methyl 3-chloro-4-hydroxy benzoate(320 mg, 1.72 mmol) and(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronicacid (E264, Step 2) using the method outlined in Example 264 Step 3 (211mg, 29%); NMR (CDCl₃) δ 1.49 (9H, s), 2.88 (4H, m), 3.56 (4H, m), 3.91(3H, s), 6.78-6.89 (3H, m), 7.12 (H, m), 7.84 (H, m), 8.14 (H, s)

Step 2:3-Chloro-4-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]benzoicacid

The title compound was prepared from 1,1-dimethylethyl7-({2-chloro-4-[(methyloxy)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylateacid (E267, Step 1) using the method outlined in Example 264 Step 4; MS(ES−), m/e 416 & 418 [M−H].

Step 3: 1,1-Dimethylethyl7-({2-chloro-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

The title compound was prepared from3-chloro-4-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]benzoicacid (E267, Step 2) and methylamine using the method outlined in Example264 Step 5 (82 mg, 52%); MS (ES+), m/e 431 & 433 [M+H]⁺.

Step 4:3-Chloro-N-methyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide

The title compound was prepared from 1,1-dimethylethyl7-({2-chloro-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E267, Step 3) using the method outlined in Example 264 Step 6 (54 mg,94%); MS (ES+), m/e 331 & 333 [M+H]⁺.

Step 5:3-Chloro-4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide

The title compound was prepared from3-chloro-N-methyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide(E267, Step 4) and cyclobutanone using the method outlined in Example264 Step 7 (36 mg, 57%) MS (ES+), m/e 385 & 387 [M+H]⁺.

Example 2684-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,3-dimethylbenzamide (E268)

Step 1: 1,1-Dimethylethyl7-({2-methyl-4-[(methyloxy)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

The title compound was prepared from7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) and methyl4-bromo-3-methylbenzoate using the method outlined in Example 128 (211mg, 29%); NMR (CDCl₃) δ 1.49 (9H, s), 2.32 (3H, m), 2.86 (4H, m), 3.55(4H, m), 3.89 (3H, s), 6.71-6.81 (3H, m), 7.08 (H, m), 7.80 (H, m), 7.94(H, s)

Step 2:4-[(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-methylbenzoicacid

The title compound was prepared from 1,1-dimethylethyl7-({2-methyl-4-[(methyloxy)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E268, Step 1) using the method outlined in Example 264 Step 4; (247 mg,94%) MS (ES−), m/e 396 [M−H].

Step 3: 1,1-Dimethylethyl7-({2-methyl-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

The title compound was prepared from4-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-methylbenzoicacid (E268, Step 2) and methylamine using the method outlined in Example264 Step 5 (136 mg, 53%); MS (ES+), m/e 411 [M+H]⁺.

Step 4:N,3-Dimethyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide

The title compound was prepared from 1,1-dimethylethyl7-({2-methyl-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E268, Step 3) using the method outlined in Example 264 Step 6 (90 mg,88%); MS (ES+), m/e 311 [M+H]⁺.

Step 5:4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,3-dimethylbenzamide

The title compound was prepared fromN,3-dimethyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide(E268, Step 4) (90 mg, 0.29 mmol) and cyclobutanone (50 μl, 0.58 mmol)using the method outlined in Example 264 Step 7 (71 mg, 67%); MS (ES+),m/e 365 [M+H]⁺.

Example 269 3-Cyclobutyl-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbonitrile (E269)

A mixture of3-cyclobutyl-7-iodo-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E226) (250 mg, 0.58 mmol), tetrakis(triphenylphosphine)palladium (0)(33 mg, 0.029 mmol), copper (I) iodide (11 mg, 0.058 mmol) and sodiumcyanide (56 mg, 1.15 mmol) in tetrahydrofuran (5 ml) was heated atreflux for 16 hours. The mixture was cooled and diluted with ethylacetate, filtered through celite, washed with water then brine and driedover sodium sulfate and concentrated in vacuo. The crude mixture waspurified by reverse phase HPLC to afford the title compound; MS (ES+)m/e 333 [M+H]⁺.

Example 2703-Cyclobutyl-7-[(2-fluorophenyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E270)

Example 270 (E270) was prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 2-fluoroiodobenzene using the method described for Example 128; MS (ES+) m/e 312[M+H]⁺.

Example 2714-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzonitrile(E271)

A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3)(100 mg, 0.46 mmol), 3,4-difluorobenzonitrile (70 mg, 0.51 mmol) andpotassium carbonate (159 mg, 1.15 mmol) in dimethylsulfoxide (2 ml) washeated at 85° C. for 2 hours. The reaction mixture was cooled andapplied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) andwashed with methanol and then a mixture of 0.880 ammonia/methanol (1:9).The combined basic fractions were concentrated in vacuo to afford thetitle compound (E271). MS (ES+) m/e 337 [M+H]⁺.

Example 2724-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzoicacid (E272)

4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzonitrile(E271) (150 mg, 0.45 mmol) was dissolved in a mixture of ethanol (1 ml)and water (1.5 ml), treated with sodium hydroxide (150 mg, 4.5 mmol) andheated at reflux for 2 hours. The reaction was then treated with aceticacid (0.39 ml, 6.75 mmol) and concentrated in vacuo. The resultingresidue was purified by column chromatography eluting with a mixture of0.880 ammonia:methanol:dichloromethane (2:18:80) to afford the titlecompound. MS (ES+) m/e 356 [M+H]⁺.

Example 2734-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluoro-N-methylbenzamide(E273)

A solution of4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzoicacid (E272) (164 mg, 0.36 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (438 mg, 1.15 mmol) in dimethylformamide (2 ml) wastreated with diisopropyl ethylamine (0.40 ml, 2.3 mmol) followed by a 2Mmethylamine solution in tetrahydrofuran (2 ml). The reaction was stirredat room temperature for 4 hours, applied to a SCX ion exchange column(Varian bond-elute, 10 g) and washed with methanol and then a mixture of0.880 ammonia/methanol, and the basic fractions concentrated in vacuo.The resulting residue was purified by column chromatography eluting witha mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) toafford the title compound. MS (ES+) m/e 369 [M+H]⁺.

Example 2743-Cyclobutyl-7-[(2-fluoro-4-iodophenyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E274)

Step 1: 1,1-Dimethylethyl7-[(2-fluoro-4-nitrophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

3,4-difluoronitrobenzene (664 mg, 4.18 mmol) was added to a mixture of7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acidtert-butyl ester (WO 02/40471) (1 g, 3.8 mmol) and potassium carbonate(1.3 g, 9.49 mmol) in dimethylformamide (10 ml) and the reaction heatedat 130° C. for 3 hours. The reaction was cooled, diluted with ethylacetate, washed with water and then with a mixture of water:brine (1:1),dried over sodium sulfate and concentrated in vacuo. The resultingresidue was purified by column chromatography eluting with a mixture ofethyl acetate:pentane (1:10) to afford the title compound. MS (ES+) m/e303 [M-COOtBu]⁺.

Step 2: 1,1-Dimethylethyl7-[(4-amino-2-fluorophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

To a solution of 1,1-dimethylethyl7-[(2-fluoro-4-nitrophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E274, Step 1) (1.37 g, 3.40 mmol) in ethanol (25 ml) was addedpalladium on charcoal (10 wt % palladium) (300 mg) and the reaction wasstirred at room temperature under hydrogen (1 atmosphere) for 3 hours.The reaction mixture was filtered through celite and concentrated invacuo to afford the title compound. MS (ES+) m/e 273 [M-M-COOtBu]⁺.

Step 3: 1,1-Dimethylethyl7-[(2-fluoro-4-iodophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

To a solution of 1,1-dimethylethyl7-[(4-amino-2-fluorophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E274, Step 2) (0.5 g, 1.34 mmol) and iodoform (1 g, 2.69 mmol) intetrahydrofuran (10 ml) was added dropwise tert-butyl nitrite (0.32 ml,2.69 mmol). The reaction was then heated at reflux for 1 hour, cooledand concentrated in vacuo and resulting residue was purified by columnchromatography eluting with a mixture of ethyl acetate:pentane (1:10) toafford the title compound. MS (ES+) m/e 384 [M-COOtBu]⁺.

Step 4:7-[(2-Fluoro-4-iodophenyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine

The title compound was prepared from 1,1-dimethylethyl7-[(2-fluoro-4-iodophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E274, Step 3) using an analogous method to that described forDescription 2 (D2). MS (ES+) m/e 384 [M+H]⁺.

Step 5:3-Cyclobutyl-7-[(2-fluoro-4-iodophenyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine

The title compound was prepared from7-[(2-fluoro-4-iodophenyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E274, Step 4) using an analogous method to that described for Example 1(E1). MS (ES+) m/e 438 [M+H]⁺.

Example 2751-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorophenyl}-2-pyrrolidinone(E275)

The title product was prepared from3-cyclobutyl-7-[(2-fluoro-4-iodophenyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E274) using an analogous method to that described for Example 258(E258). MS (ES+) m/e 395 [M+H]⁺.

Example 276N-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorophenyl}acetamide(E276)

Step 1: 1,1-Dimethylethyl7-{[4-(acetylamino)-2-fluorophenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

To a solution of 1,1-dimethylethyl7-[(4-amino-2-fluorophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E274, Step 2) (250 mg, 0.67 mmol) in dichloromethane (10 ml) was addedtriethylamine (0.19 ml, 1.34 mmol) and acetyl chloride (50 μL, 0.74 ml)and the reaction stirred at room temperature for 16 hours. The reactionwas then diluted with dichloromethane and washed with a 3N aqueoussolution of citric acid, then saturated sodium bicarbonate then waterand the dichloromethane dried over sodium sulfate and concentrated invacuo. The resulting residue was purified by column chromatographyeluting with a mixture of ethyl acetate:pentane (1:1) to afford thetitle compound. MS (ES+) m/e 413 [M−H]⁻.

Step 2:N-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorophenyl}acetamide

The title compound was prepared from 1,1-dimethylethyl7-{[4-(acetylamino)-2-fluorophenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E276, Step 1) via an analogous 2 step procedure described in Example274 steps 4-5. MS (ES+) m/e 369 [M+H]⁺.

Example 277

Example 277 (E277) was prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and theappropriate aromatic iodide indicated in the table using an analogousmethod to that described for Example 128 (E128):

LC/MS Example Aromatic Iodide [M + H]⁺ 1-[3-(3-Cyclobutyl-2,3,4,5-1-[(3- 391 tetrahydro-1H-benzo[d]azepin-7- Iodophenyl)carbonyl]yloxy)-phenyl]-1-pyrrolidin-1-yl- pyrrolidine (D52) methanone (E277)

Example 278

Example 278 (E278) was prepared from5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyridinecarboxylicacid (E187a) and the appropriate amine indicated in the table using ananalogous method to that described for Example 177 (E177):

LC/MS Example Amine [M + H]⁺ 5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-Tetrahydro-2H- 422 3-benzazepin-7-yl)oxy]-N-(tetrahydro- pyran-4-amine2H-pyran-4-yl)-2-pyridinecarboxamide (E278)

Example 2793-Cyano-4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide(E279)

Step 1: 3-Cyano-4-(methyloxy)benzoic acid

The title compound was prepared from methyl3-cyano-4-(methyloxy)benzoate using the method of Example 264 Step 4; ¹HNMR (CDCl₃) 8.32 (1H, d), 8.29-8.27 (1H, dd), 7.06-7.04 (1H, d), 4.03(3H, s).

Step 2: 3-Cyano-N-methyl-4-(methyloxy)benzamide

The title compound was prepared from 3-cyano-4-(methyloxy)benzoic acid(E279, Step 1), using the method of Example 264 Step 5; MS (ES+) m/e 191[M+H]⁺.

Step 3: 3-Cyano-4-hydroxy-N-methylbenzamide

3-Cyano-N-methyl-4-(methyloxy)benzamide (E279, Step 2) (346 mg, 1.82mmol), was dissolved in dry dichloromethane (10 ml), cooled to 0° C. andtreated with boron tribromide (1 M solution in dichloromethane) (9.11ml, 9.11 mmol). The mixture was stirred for 30 minutes, allowed to warmto room temperature and stirred for 18 hours. The mixture was cooled inan ice bath, treated with water added dropwise and then allowed to warmto room temperature. The mixture was poured onto 2M hydrochloric acid(10 ml) and extracted with ethyl acetate. The ethyl acetate layers werecombined, dried under magnesium sulfate and evaporated in vacuo. Theresulting residue was purified by column chromatography eluting with amixture of ethyl acetate dichloromethane (1:1) to afford the titlecompound (86 mg); MS (ES+) m/e 177 [M+H]⁺.

Step 4: 1,1-Dimethylethyl7-({2-cyano-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate

The title compound was prepared from 3-cyano-4-hydroxy-N-methylbenzamide(E279, Step 3) and(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronicacid (E264, Step 2), using the method of Example 264 Step 3; MS (ES+)m/e 322 [(M+H)—CO₂ ^(t)Bu]⁺.

Step 5:3-Cyano-N-methyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide

The title compound was prepared from 1,1-dimethylethyl7-({2-cyano-4-[(methylamino)carbonyl]phenyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate(E279, Step 4) using the method of Example 264 Step 6; MS (ES+) m/e 322[M+H]⁺.

Step 6:3-Cyano-4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide

The title compound was prepared from3-cyano-N-methyl-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide(E279, Step 5), using the method of Example 264 Step 7; MS (ES+) m/e 376[M+H]⁺.

Example 2803-Cyclobutyl-7-{[6-(4-morpholinylcarbonyl)-3-pyridazinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E280)

Step 1: 4-[(6-Chloro-3-pyridazinyl)carbonyl]morpholine

A mixture of 6-oxo-1,6-dihydro-3-pyridazinecarboxylic acid (A. E Mouradet al J. Het. Chem 1992; 29 (6), 1583-1592; 0.5 g) in phosphorusoxychloride (2 ml) was heated under reflux for 2 h. Excess phosphorusoxychloride was evaporated and THF (5 ml) added to the residue. Thesolution was then cooled to 0° C. and triethylamine (1.1 ml) added,followed by morpholine (1.87 ml). The mixture was allowed to warm toroom temperature, stirred for 16 h then diluted with ethyl acetate (10ml) and filtered. The filtrate was evaporated and purified bychromatography on silica gel, eluting with ethyl acetate to afford thetitle compound; MS (ES+) m/e 228 [M+H]⁺.

Step 2:3-Cyclobutyl-7-{[6-(4-morpholinylcarbonyl)-3-pyridazinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol (E3)(84 mg, 0.385 mmol), 4-[(6-chloro-3-pyridazinyl)carbonyl]morpholine(E280, Step 1) (70 mg, 0.308 mmol) and potassium carbonate (85 mg, 0.616mmol) in dry acetone (3 ml) was heated at 140° C. for 2×15 mins. (300 W)in a microwave reactor. The cooled reaction mixture was filtered,concentrated in vacuo. and Purified by column chromatography on silicagel, eluting with a mixture of 0.880 ammonia:methanol:dichloromethane(0.5:4.5:190) to afford the title compound; MS (ES+) m/e 409 [M+H]⁺.

Examples 281-282

Examples 281-282 (E281-282) were prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol (E3) and6-oxo-1,6-dihydro-3-pyridazinecarboxylic acid using the appropriateamine as indicated in the table using the two step procedure asdescribed for Example 280:

LC/MS (M + Example Amine H⁺⁾ 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-Methylamine 353 benzazepin-7-yl)oxy]-N-methyl-3- pyridazinecarboxamide(E281) 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3- Ethyl(methyl)amine 381benzazepin-7-yl)oxy]-N-ethyl-N-methyl-3- pyridazinecarboxamide (E282)

Example 2833-Cyclobutyl-7-{[4-(4-morpholinyl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E283)

Step 1:4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoicacid

Ethyl4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoate(E167a) (2.2 g, 6.6 mmol) was dissolved in methanol (40 ml) and treatedwith 2N sodium hydroxide (10.0 ml). After stirring at reflux for 1 hour,the reaction mixture was cooled to room temperature and concentrated invacuo. The crude mixture was applied to a SCX ion exchange cartridge(Varian bond-elute) and washed with water and then methanol. The organicfractions were reduced in vacuo to afford the title compound (E283); MS(ES+) m/e 304 [M+H]⁺.

Step 2:3-Cyclobutyl-7-{[4-(4-morpholinyl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine

4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoicacid (E283, Step 1) (0.15 g, 0.50 mmole) was dissolved in drydichloromethane (5 ml) and dry dimethylformamide (2 ml) was treated with1-hydroxybenzotriazole hydrate (0.14 g, 1.0 mmole) andN-cyclohexylcarbodiimide, N′-methyl polystyrene HL (0.53 g, 1.0 mmol,1.7 mmol/g) and stirred for 45 minutes. Morpholine (0.056 ml, 0.65 mmol)was added and the mixture stirred for 3 hours at ambient temperature.The crude reaction mixture was applied to a SCX ion exchange cartridge(Varian bond-elute) and washed with water, methanol and then a mixtureof 0.880 ammonia:methanol (1:9). The combined basic fractions werereduced in vacuo. The resulting residue was purified by columnchromatography eluting with a mixture of 0.880ammonia:methanol:dichloromethane (0.5:4.5:95 to 1:9:90) to afford thetitle compound (E283); MS (ES+) m/e 373 [M+H]⁺.

Examples 284-285

Examples 284-285 (E284-285) were prepared from3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) and the appropriate acid as indicated in the table using ananalogous method to that described for Example 13 (E13):

LC/MS Example Acid (M + H⁺⁾ 3-Cyclobutyl-7-[(1-{[4-(4-4-(4-Morpholinyl)- 490 morpholinyl)phenyl]carbonyl}-4- benzoic acidpiperidinyl)oxy]-2,3,4,5-tetrahydro- 1H-3-benzazepine (E284)3-Cyclobutyl-7-{[1- Cyclopropylacetic acid 383 (cyclopropylacetyl)-4-piperidinyl]oxy}-2,3,4,5-tetrahydro- 1H-3-benzazepine (E285)

Example 2863-Cyclobutyl-7-[(1-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl}-4-piperidinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine(E286)

Example 286 (E286) was prepared from3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) and cis-2,6-dimethylmorpholine using the method described forExample 61 (E61); MS (ES+) m/e 442 [M+H]⁺.

Example 2873-Cyclobutyl-7-{[trans-4-(4-morpholinylcarbonyl)cyclohexyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E287)

Example 287 (E287) was prepared from3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(E6) and cis-4-(4-morpholinylcarbonyl)-cyclohexanol (D55) using themethod described for Example 5a (E5a); MS (ES+) m/e 413 [M+H]⁺.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

Example 2883-Cyclobutyl-7-{[6-(4-morpholinyl)-2-pyrazinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine(E288)

Example (E288) was prepared from3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and4-(6-chloro-2-pyrazinyl)morpholine [Zagulyaeva, . A., J. Org. Chem.USSR, EN, 14; 1978; 377-380] using an analogous method to that describedfor Example 242 (E242); MS (ES+) m/e 381 [M+H]⁺.

Biological Data

A membrane preparation containing histamine H3 receptors may be preparedin accordance with the following procedures:

(i) Generation of Histamine H3 Cell Line

DNA encoding the human histamine H3 gene (Huvar, A. et al. (1999) Mol.Pharmacol. 55(6), 1101-1107) was cloned into a holding vector, pcDNA3.1TOPO (InVitrogen) and its cDNA was isolated from this vector byrestriction digestion of plasmid DNA with the enzymes BamH1 and Not-1and ligated into the inducible expression vector pGene (InVitrogen)digested with the same enzymes. The GeneSwitch™ system (a system wherein transgene expression is switched off in the absence of an inducer andswitched on in the presence of an inducer) was performed as described inU.S. Pat. Nos. 5,364,791; 5,874,534; and 5,935,934. Ligated DNA wastransformed into competent DH5α E. coli host bacterial cells and platedonto Luria Broth (LB) agar containing Zeocin™ (an antibiotic whichallows the selection of cells expressing the sh ble gene which ispresent on pGene and pSwitch) at 50 μg ml⁻¹. Colonies containing there-ligated plasmid were identified by restriction analysis. DNA fortransfection into mammalian cells was prepared from 250 ml cultures ofthe host bacterium containing the pGeneH3 plasmid and isolated using aDNA preparation kit (Qiagen Midi-Prep) as per manufacturers guidelines(Qiagen).

CHO K1 cells previously transfected with the pSwitch regulatory plasmid(InVitrogen) were seeded at 2×10e6 cells per T75 flask in CompleteMedium, containing Hams F12 (GIBCOBRL, Life Technologies) mediumsupplemented with 10% v/v dialysed foetal bovine serum, L-glutamine, andhygromycin (100 μg ml⁻¹), 24 hours prior to use. Plasmid DNA wastransfected into the cells using Lipofectamine plus according to themanufacturers guidelines (InVitrogen). 48 hours post transfection cellswere placed into complete medium supplemented with 500 μg ml⁻¹ Zeocin™.

10-14 days post selection 10 nM Mifepristone (InVitrogen), was added tothe culture medium to induce the expression of the receptor. 18 hourspost induction cells were detached from the flask using ethylenediaminetetra-acetic acid (EDTA; 1:5000; InVitrogen), following several washeswith phosphate buffered saline pH 7.4 and resuspended in Sorting Mediumcontaining Minimum Essential Medium (MEM), without phenol red, andsupplemented with Earles salts and 3% Foetal Clone II (Hyclone).Approximately 1×10e7 cells were examined for receptor expression bystaining with a rabbit polyclonal antibody, 4a, raised against theN-terminal domain of the histamine H3 receptor, incubated on ice for 60minutes, followed by two washes in sorting medium. Receptor boundantibody was detected by incubation of the cells for 60 minutes on icewith a goat anti rabbit antibody, conjugated with Alexa 488 fluorescencemarker (Molecular Probes). Following two further washes with SortingMedium, cells were filtered through a 50 μm Filcon™ (BD Biosciences) andthen analysed on a FACS Vantage SE Flow Cytometer fitted with anAutomatic Cell Deposition Unit. Control cells were non-induced cellstreated in a similar manner. Positively stained cells were sorted assingle cells into 96-well plates, containing Complete Medium containing500 μg ml⁻¹ Zeocin™ and allowed to expand before reanalysis for receptorexpression via antibody and ligand binding studies. One clone, 3H3, wasselected for membrane preparation.

(ii) Membrane Preparation from Cultured Cells

All steps of the protocol are carried out at 4° C. and with pre-cooledreagents. The cell pellet is resuspended in 10 volumes of buffer A2containing 50 mM N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid(HEPES) (pH 7.40) supplemented with 10e−4M leupeptin(acetyl-leucyl-leucyl-arginal; Sigma L2884), 25 μg/ml bacitracin (SigmaB0125), 1 mM ethylenediamine tetra-acetic acid (EDTA), 1 mMphenylmethylsulfonyl fluoride (PMSF) and 2×10e−6M pepstain A (Sigma).The cells are then homogenised by 2×15 second bursts in a 1 liter glassWaring blender, followed by centrifugation at 500 g for 20 minutes. Thesupernatant is then spun at 48,000 g for 30 minutes. The pellet isresuspended in 4 volumes of buffer A2 by vortexing for 5 seconds,followed by homogenisation in a Dounce homogeniser (10-15 strokes). Atthis point the preparation is aliquoted into polypropylene tubes andstored at −70° C.

Compounds of the invention may be tested for in vitro biologicalactivity in accordance with the following assays:

(I) Histamine H3 Binding Assay

For each compound being assayed, in a white walled clear bottom 96 wellplate, is added: —

(a) 10 μl of test compound (or 10 μl of iodophenpropit (a knownhistamine H3 antagonist) at a final concentration of 10 mM) diluted tothe required concentration in 10% DMSO;

(b) 10 μl ¹²⁵I 4-[3-(4-iodophenylmethoxy)propyl]-1H-imidazolium(iodoproxyfan) (Amersham;

1.85 MBq/μl or 50 μCi/ml; Specific Activity ˜2000 Ci/mmol) diluted to200 μM in assay buffer

(50 mM Tris(hydroxymethyl)aminomethane buffer (TRIS) pH 7.4, 0.5 mMethylenediamine tetra-acetic acid (EDTA)) to give 20 μM finalconcentration; and

(c) 80 μl bead/membrane mix prepared by suspending ScintillationProximity Assay (SPA) bead type WGA-PVT at 100 mg/ml in assay bufferfollowed by mixing with membrane (prepared in accordance with themethodology described above) and diluting in assay buffer to give afinal volume of 80 μl which contains 7.5 μg protein and 0.25 mg bead perwell—mixture was pre-mixed at room temperature for 60 minutes on aroller.

The plate is shaken for 5 minutes and then allowed to stand at roomtemperature for 3-4 hours prior to reading in a Wallac Microbeta counteron a 1 minute normalised tritium count protocol. Data was analysed usinga 4-parameter logistic equation.

(II) Histamine H3 Functional Antagonist Assay

For each compound being assayed, in a white walled clear bottom 96 wellplate, is added:—

(a) 10 μl of test compound (or 10 μl of guanosine 5′-triphosphate (GTP)(Sigma) as non-specific binding control) diluted to requiredconcentration in assay buffer (20 mMN-2-Hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)+100 mMNaCl+10 mM MgCl₂, pH7.4 NaOH);(b) 60 μl bead/membrane/GDP mix prepared by suspending wheat germagglutinin-polyvinyltoluene (WGA-PVT) scintillation proximity assay(SPA) beads at 100 mg/ml in assay buffer followed by mixing withmembrane (prepared in accordance with the methodology described above)and diluting in assay buffer to give a final volume of 60 μl whichcontains 10 g protein and 0.5 mg bead per well—mixture is pre-mixed at4° C. for 30 minutes on a roller and just prior to addition to theplate, 10 μM final concentration of guanosine 5′ diphosphate (GDP)(Sigma; diluted in assay buffer) is added;

The plate is incubated at room temperature to equilibrate antagonistwith receptor/beads by shaking for 30 minutes followed by addition of:

(c) 10 μl histamine (Tocris) at a final concentration of 0.3 μM; and

(d) 20 μl guanosine 5′ [γ35-S] thiotriphosphate, triethylamine salt(Amersham; radioactivity concentration=37 kBq/μl or 1 mCi/ml; SpecificActivity 1160 Ci/mmol) diluted to 1.9 nM in assay buffer to give 0.38 nMfinal.

The plate is then incubated on a shaker at room temperature for 30minutes followed by centrifugation for 5 minutes at 1500 rpm. The plateis read between 3 and 6 hours after completion of centrifuge run in aWallac Microbeta counter on a 1 minute normalised tritium countprotocol. Data is analysed using a 4-parameter logistic equation. Basalactivity used as minimum i.e. histamine not added to well.

Results

The compounds of Examples E1-3, E5-149, E151-230, E233-235, E237-256,E258, E260-270, E273 and E275-288 were tested in the histamine H3functional antagonist assay and exhibited antagonism in the followingrange: 6.5-10.5 pK_(b). More particularly, the compounds of Examples 1,52, 121, 125 and 217 exhibited antagonism in the following range9.0-10.5 pK_(b). Yet more particularly, the compound of Example 121exhibited antagonism>9.5 pK_(b).

1. A method of treatment of cognitive impairments in Alzheimer'sdisease, mild cognitive impairment, age-related memory dysfunction,epilepsy, neuropathic pain, Parkinson's disease, cognitive deficit ofschizophrenia, attention deficit hyperactivity disorder, or depression,in a human, which comprises administering to said human, an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof:

wherein: R¹ represents —C₃₋₇ cycloalkyl optionally substituted by C₁₋₃alkyl; R² represents: hydrogen; —C₁₋₆ alkyl, optionally substituted by a—CO₂R⁴ or —CONR⁵R⁶ group; —X—C₃₋₈ cycloalkyl-Y-heterocyclyl;—X-aryl-Y—C₃₋₈ cycloalkyl; —X-aryl, optionally substituted by one or twohalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —CO₂R⁴, —CONR⁵R⁶, —NR⁵COR⁶, —SO₂NR⁵R⁶or cyano groups; —X-aryl-Y-heterocyclyl, optionally substituted by oneor two ═O, halogen or R⁴ groups; —X-heteroaryl, optionally substitutedby one or two halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, nitro, hydroxy,—COR⁴, —CO₂R⁴, —NR⁵R⁶, —NR⁵COR⁶, —CONR⁵R⁶ or ═O groups;—X-heteroaryl-Y-aryl, optionally substituted by a C₁₋₆ alkylsulfonyl or—NR⁵COR⁶ group; —X-heteroaryl-Y-heteroaryl, optionally substituted by aC₁₋₆ alkyl group; —X-heteroaryl-Y-heterocyclyl, optionally substitutedby one or two ═O, C₁₋₆ alkyl, hydroxy, or halogen groups;—X-heterocyclyl, optionally substituted by a C₁₋₆ alkylsulfonyl, C₁₋₆alkoxycarbonyl, —CO₂R⁴, —COR⁴ or —CONR⁵R⁶ group; —X-heterocyclyl-Y-aryl,optionally substituted by a halogen, cyano, C₁₋₆ alkylsulfonyl, R⁴ or—CONR⁵R⁶ group; —X-heterocyclyl-Y-heterocyclyl, optionally substitutedby one or two ═O or R⁴ groups; —X-heterocyclyl-Y—C₃₋₈ cycloalkyl; or—X-heterocyclyl-Y-heteroaryl, optionally substituted by one or two C₁₋₆alkyl, ═O, cyano or —CONR⁵R⁶ groups; X represents a bond or C₁₋₆ alkyl;Y represents a bond, C₁₋₆ alkyl, CO, COC₂₋₆ alkenyl, O or SO₂; R³represents halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, amino ortrifluoromethyl; n is 0, 1 or 2; and R⁴, R⁵ and R⁶ independentlyrepresent hydrogen, C₁₋₆ alkyl, —C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl, aryl, heterocyclyl or heteroaryl or —NR⁵R⁶ may represent anitrogen containing heterocyclyl group, wherein said R⁴, R⁵ and R⁶groups may be optionally substituted by 1, 2 or 3 substituents which maybe the same or different, and which are selected from the groupconsisting of halogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, amino,═O or trifluoromethyl; and wherein when R² represents —X-heterocyclyl,—X-heterocyclyl-Y—C₃₋₈ cycloalkyl, —X-heterocyclyl-Y-aryl,—X-heterocyclyl-Y-heteroaryl or —X-heterocyclyl-Y-heterocyclyl, saidheterocyclyl group is attached to X via a carbon atom.
 2. The method ofclaim 1 wherein R¹ represents unsubstituted cyclobutyl, cyclopentyl orcyclohexyl.
 3. The method of claim 1 wherein R¹ represents unsubstitutedcyclobutyl.
 4. The method of claim 1 wherein R² represents: —X-aryl,optionally substituted by one or two halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,—CO₂R⁴, —CONR⁵R⁶, —NR⁵COR⁶, —SO₂NR⁵R⁶ or cyano groups;—X-aryl-Y-heterocyclyl, optionally substituted by one or two ═O, halogenor R⁴ groups; —X-heteroaryl, optionally substituted by one or twohalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, nitro, hydroxy, —CO₂R⁴, —COR⁴,—NR⁵R⁶, —NR⁵COR⁶, —CONR⁵R⁶ or ═O groups; —X-heteroaryl-Y-heterocyclyl,optionally substituted by one or two ═O, C₁₋₆ alkyl, hydroxy or halogengroups; or —X-heterocyclyl-Y-heterocyclyl, optionally substituted by oneor two ═O or R⁴ groups.
 5. The method of claim 4 wherein R² represents:—X-aryl, optionally substituted by one or two halogen, C₁₋₆ alkoxy,—CONR⁵R⁶, —NR⁵COR⁶ or cyano groups; —X-aryl-Y-heterocyclyl, optionallysubstituted by one or two ═O or halogen groups; unsubstituted—X-heterocyclyl-Y-heterocyclyl; —X-heteroaryl, optionally substituted byCON(H)(Me); or —X-heteroaryl-Y-heterocyclyl, wherein said heterocyclylgroup is optionally substituted by an ═O group.
 6. The method of claim 5wherein R² represents: -phenyl, optionally substituted by one or twofluorine, methoxy, —CON(H)(Me), —NHCOMe or cyano groups;-phenyl-pyrrolidinyl, optionally substituted by one or two ═O orfluorine groups; unsubstituted-piperidinyl-CO-morpholinyl; -2-pyridinylor -2-pyrazinyl, optionally substituted by CON(H)(Me); or-2-pyridinyl-N-pyrrolidinyl, wherein said pyrrolidinyl group isoptionally substituted by an ═O group.
 7. The method of claim 6 whereinR² represents 4-methylaminocarbonylpyridin-2-yl.
 8. The method of claim1 wherein X represents a bond or —CH₂—.
 9. The method of claim 8 whereinX represents a bond.
 10. The method of claim 1 wherein Y represents abond, CO, SO₂ or —CO—CH═CH—.
 11. The method of claim 10 wherein Yrepresents a bond.
 12. The method of claim 1 wherein R⁴ representshydrogen, C₁₋₆ alkyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl, aryl, heterocyclyl orheteroaryl, optionally substituted by a halogen or C₁₋₆ alkoxy group.13. The method of claim 1 wherein R⁵ and R⁶ independently representhydrogen, C₁₋₆ alkyl, —C₃₋₈ cycloalkyl, —C₁₋₆ alkyl-C₃₋₈ cycloalkyl,aryl or heterocyclyl, optionally substituted by a halogen, cyano or C₁₋₆alkoxy group; or —NR⁵R⁶ represents a nitrogen containing heterocyclylgroup, optionally substituted by one or two ═O groups.
 14. The method ofclaim 13 wherein R⁵ and R⁶ independently represent hydrogen, C₁₋₆ alkyl,—C₃₋₈ cycloalkyl or —C₁₋₆ alkyl-C₃₋₈ cycloalkyl.
 15. The method of claim1 wherein n represents 0 or
 1. 16. The method of claim 15 wherein nrepresents 1 and R³ represents a halogen atom or a cyano group.
 17. Themethod of claim 15 wherein n represents
 0. 18. The method of claim 1wherein said compound is selected from the group consisting of:7-Benzyloxy-3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine;7-Benzyloxy-3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol;3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol;4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzoazepin-7-yloxy)-piperidine-1-carboxylic acid-tert-butyl ester;3-Cyclopentyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-(piperidin-4-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-((R)-1-pyrrolidin-2-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-((R)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-((S)-pyrrolidin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-((S)-1-pyrrolidin-2-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclopentyl-7-(piperidin-4-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;4-{1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-methanoyl}-benzonitrile;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-(tetrahydro-pyran-4-yl)-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-cyclohexyl-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-isoquinolin-1-yl-methanone;4-{(E)-3-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-3-oxo-propenyl}-benzonitrile;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-isoquinolin-6-yl-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-(5-methyl-isoxazol-3-yl)-methanone;1-Benzothiazol-6-yl-1-[4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-pyridin-4-yl-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-[4-(1-pyrrolidin-1-yl-methanoyl)-phenyl]-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-thiophen-3-yl-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-furan-3-yl-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-piperidin-1-yl]-1-tetrahydro-pyran-4-yl)-methanone;1-[(R)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-pyrrolidin-1-yl]-1-(tetrahydro-pyran-4-yl)-methanone;1-[(R)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrrolidin-1-yl]-1-(tetrahydro-pyran-4-yl)-methanone;1-[(S)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrrolidin-1-yl]-1-(tetrahydro-pyran-4-yl)-methanone;1-[(S)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzoazepin-7-yloxy)-pyrrolidin-1-yl]-1-(tetrahydro-pyran-4-yl)-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-(methanesulfonyl-phenyl)-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-pyrazin-2-yl-methanone;5-{1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-methanoyl}-1H-pyridone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-(2,3-dihydro-benzofuran-5-yl)-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-3-methoxy-propan-1-one;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-(2,3-dihydro-benzofuran-7-yl)-methanone;4-{1-[4-(3-Cyclopentyl-7-(piperidin-4-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)piperidin-1-yl]-methanoyl}-benzonitrile;1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-piperidin-1-yl]-1-[4-(1-pyrrolidin-1-yl-methanoyl)-phenyl]-methanone;4-{1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-methanoyl}-benzonitrile;1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-pyridin-4-yl-methanone;1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-quinolin-6-yl-methanone;1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-[4-(1-pyrrolidin-1-yl-methanoyl)-phenyl]methanone;1-Biphenyl-4-yl-1-[4-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-cyclopentyl-methanone;4-{1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-piperidin-1-yl]-methanoyl}-benzonitrile;4-{1-[(R)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-pyrrolidin-1-yl]-methanoyl}-benzonitrile;4-{1-[(R)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrrolidin-1-yl]-methanoyl}-benzonitrile;4-{1-[(S)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrrolidin-1-yl]-methanoyl}-benzonitrile;4-{1-[(S)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrrolidin-1-yl]-methanoyl}-benzonitrile;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-2,2-dimethyl-propan-1-one;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-cyclopropyl-methanone;1-Cyclobutyl-1-[4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-yl]-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-morpholin-4-yl-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-piperidin-1-yl]-1-morpholin-4-yl-methanone;1-[(R)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-pyrrolidin-1-yl]-1-morpholin-4-yl-methanone;1-[(R)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrrolidin-1-yl]-1-morpholin-4-yl-methanone;1-[(S)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrrolidin-1-yl]-1-morpholin-4-yl-methanone;4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylicacid diisopropylamide;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-pyrrolidin-1-yl-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-piperidin-1-yl-methanone;1-[(S)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-pyrrolidin-1-yl]-1-morpholin-4-yl-methanone;4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylicacid diethylamide;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-(1,3-dihydro-isoindol-2-yl)-methanone;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-1-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-methanone;4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylicacid isopropyl-(2-methoxy-ethyl) amide;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidin-1-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone;4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylicacid isopropylamide;4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylicacid (4-fluoro-phenyl)-amide;2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N,N-dimethyl-acetamide;2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-phenyl-acetamide;2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-1-pyrrolidin-1-yl-ethanone;2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-1-morpholin-4-yl-ethanone;3-Cyclobutyl-7-(1-methanesulfonyl-piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;4-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-sulfonyl]-benzonitrile;3-Cyclobutyl-7-[1-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yloxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepine;4-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-piperidine-1-sulfonyl]-benzonitrile;4-[(R)-2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-pyrrolidine-1-sulfonyl]-benzonitrile;4-[(R)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrrolidine-1-sulfonyl]-benzonitrile;4-[(S)-3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrrolidine-1-sulfonyl]-benzonitrile;3-Cyclobutyl-7-(2,4-difluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzonitrile;3-Cyclobutyl-7-(3-methoxy-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-(pyridin-2-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-(pyridin-3-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-(pyridin-4-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzonitrile;4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzonitrile;6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-1-methyl-1H-quinolin-2-one;4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid methyl ester;4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid;1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-phenyl]-1-pyrrolidin-yl-methanone;1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzoazepin-7-yloxymethyl)-phenyl]-1-morpholin-4-yl-methanone;1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-phenyl]-1-(4-pyridin-4-yl-piperazin-1-yl)-methanone;1-[4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-phenyl]-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone;3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoicacid methyl ester;3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acid;1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-phenyl]-1-pyrrolidin-yl-methanone;1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-phenyl]-1-morpholin-4-yl-methanone;1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-phenyl]-1-(4-pyridin-4-yl-piperazin-1-yl)-methanone;1-[3-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-phenyl]-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone;6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotinonitrile;3-Cyclobutyl-7-(pyridin-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-3-yl]-1-morpholin-4-yl-methanone;1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-3-yl]-1-pyrrolidin-1-1-methanone;6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotinamide;6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N,N-dimethyl-nicotinamide;6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-ethyl-N-methyl-nicotinamide;6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-cyclopentyl-nicotinamide;1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-3-yl]-1-piperidin-1-yl-methanone;1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzoazepin-7-yloxy)-pyridin-4-yl]-1-piperidin-1-yl-methanone;1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-4-yl]-1-pyrrolidin-1-yl-methanone;1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-4-yl]-1-morpholin-4-yl-methanone;1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-2-yl]-1-piperidin-1-yl-methanone;1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-2-yl]-1-(1,1-dioxothiomorpholin-4-yl)-methanone;1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-2-yl]-1-pyrrolidin-1-yl-methanone;1-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-2-yl]-1-morpholin-4-yl-methanone;1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-3-yl]-1-morpholin-4-yl-methanone;1-[2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-3-yl]-1-piperidin-1-yl-methanone;3-Cyclobutyl-7-(pyrazin-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-(pyrimidin-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;7-(5-Bromo-pyrimidin-2-yloxy)-3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine;6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl-nicotinamide;5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylicacid methyl ester;5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylicacid;1-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazin-2-yl]-1-morpholin-4-yl-methanone;5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylicacid ethylmethyl amide;1-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazin-2-yl]-1-piperidin-4-yl-methanone;1-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazin-2-yl]-1-pyrrolidin-4-yl-methanone;5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylicacid methyl amide;3-Cyclobutyl-7-phenoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-phenyl]-1-morpholin-4-yl-methanone;4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-cyclopropylmethyl-benzamide;1-[4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-phenyl]-1-pyrrolidin-1-yl-methanone;N-Cyclobutyl-4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-benzamide;4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N,N-diethyl-benzamide;N-(2-Cyano-ethyl)-4-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl-benzamide;1-[3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-phenyl]-1-morpholin-4-yl-methanone;3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-cyclopropylmethyl-benzamide;3-Cyclobutyl-7-[4-(morpholine-4-sulfonyl)-phenoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepine;4-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N,N-diethyl-benzenesulfonamide;7-Benzyloxy-3-cyclohexyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-{[2-(1-piperidinyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[2-(1-pyrrolidinyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[2-(1,1-dioxido-4-thiomorpholinyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrimidinamine;3-Cyclobutyl-7-{[2-(methyloxy)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;1-[4-({4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}carbonyl)phenyl]-2-pyrrolidinone;3-Cyclobutyl-7-[(1-{[3-(methylsulfonyl)phenyl]carbonyl}-4-piperidinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-({1-[(1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-6-yl)carbonyl]-4-piperidinyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[(3S)-3-pyrrolidinylmethyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[(3S)-3-piperidinylmethyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-[(3S)-3-piperidinyloxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-({[(3S)-1-(4-morpholinylcarbonyl)-3-piperidinyl]methyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-({[(3S)-1-(4-morpholinylcarbonyl)-3-pyrrolidinyl]methyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[(3S)-1-(4-morpholinylcarbonyl)-3-piperidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;4-[((3S)-3-{[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]methyl}-1-piperidinyl)carbonyl]benzonitrile;4-[((35)-3-{[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]methyl}-1-pyrrolidinyl)carbonyl]benzonitrile;4-({(3S)-3-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}carbonyl)benzonitrile;3-Cyclobutyl-7-({[(3S)-1-(tetrahydro-2H-pyran-4-ylcarbonyl)-3-pyrrolidinyl]methyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-({[(3S)-1-(tetrahydro-2H-pyran-4-ylcarbonyl)-3-piperidinyl]methyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[(3S)-1-(tetrahydro-2H-pyran-4-ylcarbonyl)-3-piperidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;6-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}-3-pyridinecarbonitrile;6-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}-N-(cyclopropylmethyl)-3-pyridinecarboxamide;7-({1-[5-(1-Azetidinylcarbonyl)-2-pyridinyl]-4-piperidinyl}oxy)-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-({1-[5-(4-morpholinylcarbonyl)-2-pyridinyl]-4-piperidinyl}oxy)-2,3,4,5-tetrahydro-1H-3-benzazepine;6-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}-N-methyl-3-pyridinecarboxamide;2-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1-piperidinyl}-4-pyridinecarbonitrile;3-Cyclobutyl-7-{[1-(2-pyrazinyl)-4-piperidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;Ethyl4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoate;4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]butanoicacid;3-Cyclobutyl-7-{[4-oxo-4-(1-piperidinyl)butyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[4-oxo-4-(1-pyrrolidinyl)butyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-cyclopentylbutanamide;4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbutanamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(1-methylethyl)-2-pyrazinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(tetrahydro-2H-pyran-4-yl)-2-pyrazinecarboxamide;7-{[5-(1-Azetidinylcarbonyl)-2-pyrazinyl]oxy}-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,N-diethyl-2-pyrazinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-[2-(methyloxy)ethyl]-2-pyrazinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-2-pyrazinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarbonitrile;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarboxylicacid;3-Cyclobutyl-7-{[2-(4-morpholinylcarbonyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(cyclopropylmethyl)-2-pyrimidinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-2-pyrimidinecarboxamide;7-{[2-(1-Azetidinylcarbonyl)-5-pyrimidinyl]oxy}-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-N-methyl-2-pyrimidinecarboxamide;N-Cyclobutyl-5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(tetrahydro-2H-pyran-4-yl)-2-pyrimidinecarboxamide;3-Cyclobutyl-7-[2-(1-pyrrolidinylcarbonyl)-5-pyrimidinyl]oxy-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[2-(1-piperidinylcarbonyl)-5-pyrimidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrimidinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyridinecarboxylicacid;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyridinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-2-pyridinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-N-methyl-2-pyridinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,N-diethyl-2-pyridinecarboxamide;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-N-[2-(methyloxy)ethyl]-2-pyridinecarboxamide;3-Cyclobutyl-7-{[6-(1-pyrrolidinylcarbonyl)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[6-(4-morpholinylcarbonyl)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[6-(tetrahydro-1,4-oxazepin-4(5H)-ylcarbonyl)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-cyclopentyl-2-pyridinecarboxamide;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxylicacid methyl ester;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxylicacid;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-cyclopropyl-3-pyridinecarboxamide;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(1-methylethyl)-3-pyridinecarboxamide;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-3-pyridinecarboxamide;N-Cyclobutyl-6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxamide;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(tetrahydro-2H-pyran-4-yl)-3-pyridinecarboxamide;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,N-diethyl-3-pyridinecarboxamide;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-[2-(methyloxy)ethyl]-3-pyridinecarboxamide;4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-N-[2-(methyloxy)ethyl]benzamide;4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide;3-Cyclobutyl-7-(3-pyridinyloxy)-2,3,4,5-tetrahydro-1H-3-benzazepine;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyridinecarbonitrile;3-Cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-[(5-nitro-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;N-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}acetamide;3-Cyclobutyl-7-[(5-nitro-1,3-thiazol-2-yl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;N-{2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-1,3-thiazol-5-yl}acetamide;3-Cyclobutyl-7-[(5-nitro-2-thienyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;N-{5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-thienyl}acetamide;3-Cyclobutyl-7-{[6-(methyloxy)-3-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2(1H)-pyridinone;1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}ethanone;3-Cyclobutyl-7-{[5-(1H-pyrazol-5-yl)-2-pyridinyl]oxy-}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-piperidinone;1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-azetidinone;3-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-1,3-oxazolidin-2-one;3-Cyclobutyl-7-{[5-(1H-pyrazol-1-yl)-2-pyridinyl]oxy-}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[5-(3,5-dimethyl-4-isoxazolyl)-2-pyridinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;6-[(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide;N-Methyl-6-{[3-(2-methylcyclopentyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]oxy}-3-pyridinecarboxamide;6-[(3-Cyclobutyl-8-iodo-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide;3-Cyclobutyl-7-iodo-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[6-methyl-4-(methyloxy)-2-quinolinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[4-(methyloxy)-1,7-naphthyridin-2-yl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-(1,5-naphthyridin-2-yloxy)-2,3,4,5-tetrahydro-1H-3-benzazepine;N-{7-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-6-methyl-1,8-naphthyridin-2-yl}acetamide;Dimethyl6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate;Disodium6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2,3-pyridinedicarboxylate;2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione;2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinamine;N-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-4-morpholinecarboxamide;N-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-1-piperidinecarboxamide;N-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-1-pyrrolidinecarboxamide;N-[6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-3-yl]isobutyramide;Tetrahydro-pyran-4-carboxylic acid[6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyridin-3-yl]-amide;3-Cyclobutyl-7-[5-(4-methanesulfonyl-phenyl)-pyrazine-2-yloxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepine;N-{4-[5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazin-2-yl]-phenyl}-acetamide;3-Cyclobutyl-7-(3,5-dimethyl-pyridin-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-[5-(morpholine-4-sulfonyl)-pyridin-2-yloxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepine;3-Cyclobutyl-7-(2-methyl-furo[2,3-c]pyridin-7-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine;2-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-4-ethoxy-nicotinonitrile;6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-2-methyl-nicotinonitrile;1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-5-methyl-2-pyrrolidinone;1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-3-methyl-2-imidazolidine;(4R)-1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-4-hydroxy-2-pyrrolidinone;N-Methyl-6-{[3-(3-methylcyclopentyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]oxy}-3-pyridinecarboxamide;5-[(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide;N-Methyl-5-{[3-(3-methylcyclopentyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]oxy}-2-pyrazinecarboxamide;1-{3-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinyl}-2-pyrrolidinone;7-[(5-Chloro-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine;1-{5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinyl}-2-pyrrolidinone;7-[(5-Bromo-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine;3-{5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinyl}-1,3-oxazolidin-2-one;3-Cyclobutyl-7-[5-(1,1-dioxo-2-isothiazolidin-2-yl)-pyridin-2-yloxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;1-{6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-imidazolidinone;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxamide;4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-(methyloxy)benzamide;2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]benzonitrile;3-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-4-(methyloxy)benzamide;3-Chloro-4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide;4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N,3-dimethylbenzamide;3-Cyclobutyl-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbonitrile;3-Cyclobutyl-7-[(2-fluorophenyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzonitrile;4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzoicacid;4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluoro-N-methylbenzamide;3-Cyclobutyl-7-[(2-fluoro-4-iodophenyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;1-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorophenyl}-2-pyrrolidinone;N-{4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorophenyl}acetamide;1-[3-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-phenyl]-1-pyrrolidin-1-yl-methanone;5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-(tetrahydro-2H-pyran-4-yl)-2-pyridinecarboxamide;3-Cyano-4-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methylbenzamide;3-Cyclobutyl-7-{[6-(4-morpholinylcarbonyl)-3-pyridazinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridazinecarboxamide;6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-ethyl-N-methyl-3-pyridazinecarboxamide;3-Cyclobutyl-7-{[4-(4-morpholinyl)-4-oxobutyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-[(1-{[4-(4-morpholinyl)phenyl]carbonyl}-4-piperidinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[1-(cyclopropylacetyl)-4-piperidinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-[(1-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl}-4-piperidinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[trans-4-(4-morpholinylcarbonyl)cyclohexyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;3-Cyclobutyl-7-{[6-(4-morpholinyl)-2-pyrazinyl]oxy}-2,3,4,5-tetrahydro-1H-3-benzazepine;or a pharmaceutically acceptable salt thereof.
 19. The method of claim18 wherein said compound is:5-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylicacid methyl amide; or a pharmaceutically acceptable salt thereof.